DGIdb - SIROLIMUS Drug Record

SIROLIMUS chembl:CHEMBL413 ApprovedAntineoplasticImmunotherapy

Alternate Names:

RAPAMYCIN
SIROLIMUS
L04AA10
RAPAMUNE
SM-88 COMPONENT SIROLIMUS
AY-22989
WY-090217
NSC-226080
(-)-RAPAMYCIN
drugbank:00877
chembl:CHEMBL413
pubchem.compound:5284616
rxcui:35302
chemidplus:53123-88-9

Drug Info:

Notes	rapalogue
Drug Class	Kinase Inhibitors
Drug Indications	for treatment of wet age-related macular degeneration
FDA Approval	approved
Drug Class	Small Molecule
Drug Indications	immunosuppressant
Drug Categories	therapeutic uses
Drug Categories	selective immunosuppressants
Drug Categories	polyketides
Drug Categories	polycyclic compounds
Drug Categories	physiological effects of drugs
Drug Categories	pharmacologic actions
Drug Categories	p-glycoprotein/abcb1 inhibitors
Drug Categories	p-glycoprotein/abcb1 inducers
Drug Categories	organic chemicals
Drug Categories	myelosuppressive agents
Drug Categories	macrolides
Drug Categories	macrocyclic compounds
Drug Categories	lactones
Drug Categories	immunosuppressive agents
Drug Categories	immunologic factors
Drug Categories	hyperglycemia-associated agents
Drug Categories	cytochrome p-450 cyp3a4 substrates
Drug Categories	cytochrome p-450 cyp3a inhibitors
Drug Categories	combined inhibitors of cyp3a4 and p-glycoprotein
Drug Categories	chemical actions and uses
Drug Categories	antineoplastic and immunomodulating agents
Drug Categories	antineoplastic agents
Drug Categories	antifungal agents
Drug Categories	antibiotics, antineoplastic
Drug Categories	anti-infective agents
Drug Categories	anti-bacterial agents
Drug Groups	investigational
Drug Groups	approved
Drug Type	small molecule
Drug Class	immunosuppressive agents
Year of Approval	2007
Drug Categories	sirolimus and prodrugs
Drug Categories	sensory organs
Drug Categories	protein kinase inhibitors
Drug Categories	p-glycoprotein substrates with narrow therapeutic index
Drug Categories	p-glycoprotein substrates
Drug Categories	p-glycoprotein inhibitors
Drug Categories	p-glycoprotein inducers
Drug Categories	ophthalmologicals
Drug Categories	oatp1b1/slco1b1 inhibitors
Drug Categories	narrow therapeutic index drugs
Drug Categories	mtor inhibitors
Drug Categories	mtor inhibitor immunosuppressant
Drug Categories	kinase inhibitor
Drug Categories	decreased immunologic activity
Drug Categories	cytochrome p-450 substrates
Drug Categories	cytochrome p-450 cyp3a7 substrates with a narrow therapeutic index
Drug Categories	cytochrome p-450 cyp3a7 substrates
Drug Categories	cytochrome p-450 cyp3a5 substrates with a narrow therapeutic index
Drug Categories	cytochrome p-450 cyp3a5 substrates
Drug Categories	cytochrome p-450 cyp3a4 substrates with a narrow therapeutic index
Drug Categories	cytochrome p-450 cyp3a substrates
Drug Categories	agents causing angioedema

(16 More Sources)

Publications:

Nardacci et al., 2005, Characterization of cell death pathways in human immunodeficiency virus-associated encephalitis., Am. J. Pathol.
Yamaguchi et al., 2016, A synthetic-lethality RNAi screen reveals an ERK-mTOR co-targeting pro-apoptotic switch in PIK3CA+ oral cancers., Oncotarget
Purdom-Dickinson et al., 2007, Translational control of nrf2 protein in activation of antioxidant response by oxidants., Mol. Pharmacol.
Jardim et al., 2014, FBXW7 mutations in patients with advanced cancers: clinical and molecular characteristics and outcomes with mTOR inhibitors., PLoS ONE
Mao et al., 2008, FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression., Science
Wang et al., 2013, Rapamycin inhibits FBXW7 loss-induced epithelial-mesenchymal transition and cancer stem cell-like characteristics in colorectal cancer cells., Biochem. Biophys. Res. Commun.
Nepomuceno et al., 2003, Rapamycin inhibits the interleukin 10 signal transduction pathway and the growth of Epstein Barr virus B-cell lymphomas., Cancer Res.
Sam WJ et al., 2011, Associations of ABCB1 3435C>T and IL-10-1082G>A polymorphisms with long-term sirolimus dose requirements in renal transplant patients., Transplantation
Woillard JB et al., 2013, Effect of CYP3A422, POR28, and PPARA rs4253728 on sirolimus in vitro metabolism and trough concentrations in kidney transplant recipients., Clin Chem
Liang et al., 2010, TSC1 loss synergizes with KRAS activation in lung cancer development in the mouse and confers rapamycin sensitivity., Oncogene
Avellino et al., 2005, Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells., Blood
Zick et al., 2017, Treatment inferred from mutations identified using massive parallel sequencing leads to clinical benefit in some heavily pretreated cancer patients., Medicine (Baltimore)
Engelman et al., 2008, Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers., Nat. Med.
Kang et al., 2005, Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic., Proc. Natl. Acad. Sci. U.S.A.
Gymnopoulos et al., 2007, Rare cancer-specific mutations in PIK3CA show gain of function., Proc. Natl. Acad. Sci. U.S.A.
Jung KS et al., 2017, Pilot study of sirolimus in patients with PIK3CA mutant/amplified refractory solid cancer., Mol Clin Oncol
Mavrakis et al., 2008, Tumorigenic activity and therapeutic inhibition of Rheb GTPase., Genes Dev.
Sehgal, 2003, Sirolimus: its discovery, biological properties, and mechanism of action., Transplant. Proc.
Chen et al., 2002, TTD: Therapeutic Target Database., Nucleic Acids Res.
Salomé C et al., 2014, Benzofuran derivatives as anticancer inhibitors of mTOR signaling., Eur J Med Chem
Du L et al., 2014, Cytotoxic dimeric epipolythiodiketopiperazines from the ascomycetous fungus Preussia typharum., J Nat Prod
Nowak P et al., 2009, Discovery of potent and selective inhibitors of the mammalian target of rapamycin (mTOR) kinase., J Med Chem
Pratt MR et al., 2007, Small-molecule-mediated rescue of protein function by an inducible proteolytic shunt., Proc Natl Acad Sci U S A
Chang et al., 2016, Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity., Nat. Biotechnol.
Grabiner et al., 2014, A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity., Cancer Discov
Rodrik-Outmezguine et al., 2016, Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor., Nature
Shuuin et al., 2009, [Mammalian target of rapamycin, its mode of action and clinical response in metastatic clear cell carcinoma]., Gan To Kagaku Ryoho
Dowling et al., 2010, Dissecting the role of mTOR: lessons from mTOR inhibitors., Biochim. Biophys. Acta
Lovly et al., 2011, Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors., Cancer Res.
Mungamuri et al., 2006, Survival signaling by Notch1: mammalian target of rapamycin (mTOR)-dependent inhibition of p53., Cancer Res.
Palm et al., 2015, The Utilization of Extracellular Proteins as Nutrients Is Suppressed by mTORC1., Cell
Contreras et al., Lkb1 inactivation is sufficient to drive endometrial cancers that are aggressive yet highly responsive to mTOR inhibitor monotherapy., Dis Model Mech
Nishimura S et al., 2020, Serine Threonine Kinase 11/Liver Kinase B1 Mutation in Sporadic Scirrhous-type Gastric Cancer Cells., Carcinogenesis
Brown et al., 2003, Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling., Proc. Natl. Acad. Sci. U.S.A.
Ganesan et al., 2016, Epidermal Growth Factor Receptor P753S Mutation in Cutaneous Squamous Cell Carcinoma Responsive to Cetuximab-Based Therapy., J. Clin. Oncol.
Pirazzoli et al., 2014, Acquired resistance of EGFR-mutant lung adenocarcinomas to afatinib plus cetuximab is associated with activation of mTORC1., Cell Rep
Engelman et al., 2007, PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib., Cancer Res.
MacConaill et al., 2014, Prospective enterprise-level molecular genotyping of a cohort of cancer patients., J Mol Diagn
Mbatchi LC et al., 2017, Association of NR1I2, CYP3A5 and ABCB1 genetic polymorphisms with variability of temsirolimus pharmacokinetics and toxicity in patients with metastatic bladder cancer., Cancer Chemother Pharmacol
Woillard JB et al., 2010, Risk of diarrhoea in a long-term cohort of renal transplant patients given mycophenolate mofetil: the significant role of the UGT1A8 2 variant allele., Br J Clin Pharmacol
Aoki et al., 2006, mTOR pathway inhibition attenuates skeletal muscle growth induced by stretching., Cell Tissue Res.
Maertens et al., 2013, Elucidating distinct roles for NF1 in melanomagenesis., Cancer Discov
Pawarode et al., 2007, Differential effects of the immunosuppressive agents cyclosporin A, tacrolimus and sirolimus on drug transport by multidrug resistance proteins., Cancer Chemother. Pharmacol.
Wei et al., 2006, Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance., Cancer Cell
Dunn et al., 2001, Up-regulation of urokinase-type plasminogen activator by insulin-like growth factor-I depends upon phosphatidylinositol-3 kinase and mitogen-activated protein kinase kinase., Cancer Res.
Chen et al., 1996, The RB/p107/p130 phosphorylation pathway is not inhibited in rapamycin-induced G1-prolongation of NIH3T3 cells., Oncogene
Entingh et al., 2001, Induction of the C/EBP homologous protein (CHOP) by amino acid deprivation requires insulin-like growth factor I, phosphatidylinositol 3-kinase, and mammalian target of rapamycin signaling., Endocrinology
Tirado et al., 2005, Rapamycin induces apoptosis of JN-DSRCT-1 cells by increasing the Bax : Bcl-xL ratio through concurrent mechanisms dependent and independent of its mTOR inhibitory activity., Oncogene
Cummins et al., 2004, CYP3A4-transfected Caco-2 cells as a tool for understanding biochemical absorption barriers: studies with sirolimus and midazolam., J. Pharmacol. Exp. Ther.
Sam WJ et al., 2012, Associations of ABCB1 and IL-10 genetic polymorphisms with sirolimus-induced dyslipidemia in renal transplant recipients., Transplantation
Lai et al., 1994, CD28 signaling causes a sustained down-regulation of I kappa B alpha which can be prevented by the immunosuppressant rapamycin., J. Biol. Chem.
Vanasek et al., 2001, Antagonistic roles for CTLA-4 and the mammalian target of rapamycin in the regulation of clonal anergy: enhanced cell cycle progression promotes recall antigen responsiveness., J. Immunol.
Fox et al., 2005, The Pim kinases control rapamycin-resistant T cell survival and activation., J. Exp. Med.
Renoir et al., 1992, [Effect of immunosuppressants FK506 and rapamycin on the function of progesterone receptor: protein "p59-HBI", intersection between immunology and endocrinology?]., C. R. Acad. Sci. III, Sci. Vie
Patel et al., 2002, Insulin regulation of hepatic insulin-like growth factor-binding protein-1 (IGFBP-1) gene expression and mammalian target of rapamycin (mTOR) signalling is impaired by the presence of hydrogen peroxide., Biochem. J.
Livi et al., 2013, Rapamycin extends life span of Rb1+/- mice by inhibiting neuroendocrine tumors., Aging (Albany NY)
Windle et al., 1990, Retinoblastoma in transgenic mice., Nature
Piña et al., 2011, Advanced retinoblastoma treatment: targeting hypoxia by inhibition of the mammalian target of rapamycin (mTOR) in LH(BETA)T(AG) retinal tumors., Clin Ophthalmol
Bierer et al., 1990, Probing immunosuppressant action with a nonnatural immunophilin ligand., Science
Fraser et al., 1999, The association of initiation factor 4F with poly(A)-binding protein is enhanced in serum-stimulated Xenopus kidney cells., J. Biol. Chem.
Feigenblum et al., 1996, Cap-binding protein (eukaryotic initiation factor 4E) and 4E-inactivating protein BP-1 independently regulate cap-dependent translation., Mol. Cell. Biol.
Naegele et al., 2004, Molecular cross-talk between MEK1/2 and mTOR signaling during recovery of 293 cells from hypertonic stress., J. Biol. Chem.
Davies et al., 2004, Inhibition of phosphatidylinositol 3-kinase- and ERK MAPK-regulated protein synthesis reveals the pro-apoptotic properties of CD40 ligation in carcinoma cells., J. Biol. Chem.
Tuxworth et al., 1999, Role of load in regulating eIF-4F complex formation in adult feline cardiocytes., Am. J. Physiol.
Fraser et al., 1999, Cellular stress in xenopus kidney cells enhances the phosphorylation of eukaryotic translation initiation factor (eIF)4E and the association of eIF4F with poly(A)-binding protein., Biochem. J.
Sanftner et al., 2006, Dimerizer regulation of AADC expression and behavioral response in AAV-transduced 6-OHDA lesioned rats., Mol. Ther.
Duncan et al., 2005, Signal transduction pathways leading to increased eIF4E phosphorylation caused by oxidative stress., Free Radic. Biol. Med.
Hahn-Windgassen et al., 2005, Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity., J. Biol. Chem.
Hung et al., 2010, Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment., Proc. Natl. Acad. Sci. U.S.A.
Fujishita et al., 2008, Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in ApcDelta716 mice., Proc. Natl. Acad. Sci. U.S.A.
Vanaudenaerde et al., 2007, Macrolides inhibit IL17-induced IL8 and 8-isoprostane release from human airway smooth muscle cells., Am. J. Transplant.
Rodríguez-Jiménez C et al., 2017, Influence of genetic polymorphisms of CYP3A5 and ABCB1 on sirolimus pharmacokinetics, patient and graft survival and other clinical outcomes in renal transplant., Drug Metab Pers Ther
Li Y et al., 2015, CYP3A5 and ABCB1 genotype influence tacrolimus and sirolimus pharmacokinetics in renal transplant recipients., Springerplus
Emoto C et al., 2015, The impact of CYP3A5*3 polymorphism on sirolimus pharmacokinetics: insights from predictions with a physiologically-based pharmacokinetic model., Br J Clin Pharmacol
Miao LY et al., 2008, Association study of ABCB1 and CYP3A5 gene polymorphisms with sirolimus trough concentration and dose requirements in Chinese renal transplant recipients., Biopharm Drug Dispos
Le Meur Y et al., 2006, CYP3A5*3 influences sirolimus oral clearance in de novo and stable renal transplant recipients., Clin Pharmacol Ther
Anglicheau D et al., 2005, Consequences of genetic polymorphisms for sirolimus requirements after renal transplant in patients on primary sirolimus therapy., Am J Transplant
Singleton et al., 2015, Kinome RNAi Screens Reveal Synergistic Targeting of MTOR and FGFR1 Pathways for Treatment of Lung Cancer and HNSCC., Cancer Res.
Dubois et al., 2003, Distinct pathways involving the FK506-binding proteins 12 and 12.6 underlie IL-2-versus IL-15-mediated proliferation of T cells., Proc. Natl. Acad. Sci. U.S.A.
Schalm et al., 2002, Identification of a conserved motif required for mTOR signaling., Curr. Biol.
Martin et al., 2001, Ribosomal S6 kinase 2 inhibition by a potent C-terminal repressor domain is relieved by mitogen-activated protein-extracellular signal-regulated kinase kinase-regulated phosphorylation., J. Biol. Chem.
Martin et al., 2001, Regulation of ribosomal S6 kinase 2 by effectors of the phosphoinositide 3-kinase pathway., J. Biol. Chem.
Perera et al., 2009, HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy., Proc. Natl. Acad. Sci. U.S.A.
Schaefer et al., 2007, Decorin-mediated regulation of fibrillin-1 in the kidney involves the insulin-like growth factor-I receptor and Mammalian target of rapamycin., Am. J. Pathol.
Poulalhon et al., 2006, Modulation of collagen and MMP-1 gene expression in fibroblasts by the immunosuppressive drug rapamycin. A direct role as an antifibrotic agent?, J. Biol. Chem.
Poston et al., 1999, Antisense oligodeoxynucleotides prevent acute cardiac allograft rejection via a novel, nontoxic, highly efficient transfection method., Transplantation
Ling Q et al., 2013, Association between donor and recipient TCF7L2 gene polymorphisms and the risk of new-onset diabetes mellitus after liver transplantation in a Han Chinese population., J Hepatol
Kurzawski M et al., 2011, Association of transcription factor 7-like 2 (TCF7L2) gene polymorphism with posttransplant diabetes mellitus in kidney transplant patients medicated with tacrolimus., Pharmacol Rep
Gopalan PK et al., 2018, CDK4/6 inhibition stabilizes disease in patients with p16-null non-small cell lung cancer and is synergistic with mTOR inhibition., Oncotarget

SIROLIMUS FKBP1A

Interaction Types & Directionality:

inhibitor (inhibitory)

Interaction Info:

Direct Interaction yes

Mechanism of Interaction FK506-binding protein 1A inhibitor

Details of the Assay for Interaction Measuring ability to inhibit the proteins rotamase activity

Publications:

Sehgal, 2003, Sirolimus: its discovery, biological properties, and mechanism of action., Transplant. Proc.

Chen et al., 2002, TTD: Therapeutic Target Database., Nucleic Acids Res.

Salomé C et al., 2014, Benzofuran derivatives as anticancer inhibitors of mTOR signaling., Eur J Med Chem

SIROLIMUS MTOR

Interaction Types & Directionality:

inhibitor (inhibitory)

Interaction Info:

Drug family MTOR inhibitor

Alteration MTOR:L1460P,S2215Y,R2505P

Trial Name LCP-Siro, sirolimus

Publications:

Nowak P et al., 2009, Discovery of potent and selective inhibitors of the mammalian target of rapamycin (mTOR) kinase., J Med Chem

Salomé C et al., 2014, Benzofuran derivatives as anticancer inhibitors of mTOR signaling., Eur J Med Chem

Pratt MR et al., 2007, Small-molecule-mediated rescue of protein function by an inducible proteolytic shunt., Proc Natl Acad Sci U S A

SIROLIMUS HRAS

Interaction Types & Directionality:

n/a

Interaction Info:

combination therapy Sirolimus + Trametinib

Indication/Tumor Type head and neck squamous cell carcinoma

Response Type sensitive

Publications:

Yamaguchi et al., 2016, A synthetic-lethality RNAi screen reveals an ERK-mTOR co-targeting pro-apoptotic switch in PIK3CA+ oral cancers., Oncotarget

SIROLIMUS FBXW7

Interaction Types & Directionality:

n/a

Interaction Info:

Indication/Tumor Type colon cancer

Response Type sensitive

Approval Status Preclinical

Publications:

Jardim et al., 2014, FBXW7 mutations in patients with advanced cancers: clinical and molecular characteristics and outcomes with mTOR inhibitors., PLoS ONE

Mao et al., 2008, FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression., Science

Wang et al., 2013, Rapamycin inhibits FBXW7 loss-induced epithelial-mesenchymal transition and cancer stem cell-like characteristics in colorectal cancer cells., Biochem. Biophys. Res. Commun.

SIROLIMUS PIK3CA

Interaction Types & Directionality:

n/a

Interaction Info:

Indication/Tumor Type Advanced Solid Tumor

Response Type sensitive

Approval Status Preclinical

Publications:

Avellino et al., 2005, Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells., Blood

Zick et al., 2017, Treatment inferred from mutations identified using massive parallel sequencing leads to clinical benefit in some heavily pretreated cancer patients., Medicine (Baltimore)

Yamaguchi et al., 2016, A synthetic-lethality RNAi screen reveals an ERK-mTOR co-targeting pro-apoptotic switch in PIK3CA+ oral cancers., Oncotarget

SIROLIMUS AKT1

Interaction Types & Directionality:

n/a

Interaction Info:

Response Type predicted – sensitive

combination therapy Doxorubicin + Sirolimus

Evidence Type Actionable

Publications:

Mavrakis et al., 2008, Tumorigenic activity and therapeutic inhibition of Rheb GTPase., Genes Dev.
SIROLIMUS EML4

Interaction Types & Directionality:

n/a

Interaction Info:

combination therapy Sirolimus + X-396

Indication/Tumor Type non-small cell lung carcinoma

Response Type sensitive

Publications:

Lovly et al., 2011, Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors., Cancer Res.

SIROLIMUS TP53

Interaction Types & Directionality:

n/a

Interaction Info:

Indication/Tumor Type pancreatic ductal adenocarcinoma

Response Type conflicting

Approval Status Preclinical

Publications:

Mungamuri et al., 2006, Survival signaling by Notch1: mammalian target of rapamycin (mTOR)-dependent inhibition of p53., Cancer Res.

Palm et al., 2015, The Utilization of Extracellular Proteins as Nutrients Is Suppressed by mTORC1., Cell

SIROLIMUS STK11

Interaction Types & Directionality:

n/a

Interaction Info:

Evidence Type Actionable

Approval Status Preclinical

Response Type sensitive

Publications:

Contreras et al., Lkb1 inactivation is sufficient to drive endometrial cancers that are aggressive yet highly responsive to mTOR inhibitor monotherapy., Dis Model Mech

Nishimura S et al., 2020, Serine Threonine Kinase 11/Liver Kinase B1 Mutation in Sporadic Scirrhous-type Gastric Cancer Cells., Carcinogenesis

SIROLIMUS EGFR

Interaction Types & Directionality:

n/a

Interaction Info:

Alteration EGFR:P753S

Drug family EGFR mAb inhibitor;MTOR inhibitor

combination therapy Cetuximab;Sirolimus

Publications:

Ganesan et al., 2016, Epidermal Growth Factor Receptor P753S Mutation in Cutaneous Squamous Cell Carcinoma Responsive to Cetuximab-Based Therapy., J. Clin. Oncol.

Pirazzoli et al., 2014, Acquired resistance of EGFR-mutant lung adenocarcinomas to afatinib plus cetuximab is associated with activation of mTORC1., Cell Rep

Engelman et al., 2007, PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib., Cancer Res.

SIROLIMUS FGF2

Interaction Types & Directionality:

n/a

Interaction Info:

Trial Name LCP-Siro, sirolimus

Novel drug target Established target

Publications:

Sehgal, 2003, Sirolimus: its discovery, biological properties, and mechanism of action., Transplant. Proc.
SIROLIMUS NF1

Interaction Types & Directionality:

n/a

Interaction Info:

Drug family MTOR inhibitor

Alteration NF1:del

Alteration NF1:.

Publications:

Maertens et al., 2013, Elucidating distinct roles for NF1 in melanomagenesis., Cancer Discov

SIROLIMUS RB1

Interaction Types & Directionality:

n/a

Interaction Info:

Indication/Tumor Type retinoblastoma

Response Type sensitive

Approval Status Preclinical

Publications:

Livi et al., 2013, Rapamycin extends life span of Rb1+/- mice by inhibiting neuroendocrine tumors., Aging (Albany NY)

Windle et al., 1990, Retinoblastoma in transgenic mice., Nature

Piña et al., 2011, Advanced retinoblastoma treatment: targeting hypoxia by inhibition of the mammalian target of rapamycin (mTOR) in LH(BETA)T(AG) retinal tumors., Clin Ophthalmol

SIROLIMUS KRAS

Interaction Types & Directionality:

n/a

Interaction Info:

Indication/Tumor Type pancreatic ductal adenocarcinoma

Response Type conflicting

Approval Status Preclinical

Publications:

Yamaguchi et al., 2016, A synthetic-lethality RNAi screen reveals an ERK-mTOR co-targeting pro-apoptotic switch in PIK3CA+ oral cancers., Oncotarget

Palm et al., 2015, The Utilization of Extracellular Proteins as Nutrients Is Suppressed by mTORC1., Cell

SIROLIMUS APC

Interaction Types & Directionality:

n/a

Interaction Info:

Indication/Tumor Type colon cancer

Response Type sensitive

Approval Status Preclinical

Publications:

Hung et al., 2010, Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment., Proc. Natl. Acad. Sci. U.S.A.

Fujishita et al., 2008, Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in ApcDelta716 mice., Proc. Natl. Acad. Sci. U.S.A.

SIROLIMUS FGFR1

Interaction Types & Directionality:

n/a

Interaction Info:

combination therapy AZD4547 + Sirolimus

Indication/Tumor Type lung adenocarcinoma

Response Type sensitive

Publications:

Singleton et al., 2015, Kinome RNAi Screens Reveal Synergistic Targeting of MTOR and FGFR1 Pathways for Treatment of Lung Cancer and HNSCC., Cancer Res.
SIROLIMUS CDKN2A

Interaction Types & Directionality:

n/a

Interaction Info:

Evidence Type Actionable

Approval Status Preclinical - Cell culture

Response Type sensitive

Publications:

Gopalan PK et al., 2018, CDK4/6 inhibition stabilizes disease in patients with p16-null non-small cell lung cancer and is synergistic with mTOR inhibition., Oncotarget
SIROLIMUS PTEN

Interaction Types & Directionality:

n/a

Interaction Info:

Drug family MTOR inhibitor

Alteration PTEN:del

Alteration PTEN:.

Publications:
SIROLIMUS TGM2

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Nardacci et al., 2005, Characterization of cell death pathways in human immunodeficiency virus-associated encephalitis., Am. J. Pathol.
SIROLIMUS NFE2L2

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Purdom-Dickinson et al., 2007, Translational control of nrf2 protein in activation of antioxidant response by oxidants., Mol. Pharmacol.

SIROLIMUS IL10

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Nepomuceno et al., 2003, Rapamycin inhibits the interleukin 10 signal transduction pathway and the growth of Epstein Barr virus B-cell lymphomas., Cancer Res.

Sam WJ et al., 2011, Associations of ABCB1 3435C>T and IL-10-1082G>A polymorphisms with long-term sirolimus dose requirements in renal transplant patients., Transplantation

SIROLIMUS POR

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Woillard JB et al., 2013, Effect of CYP3A4*22, POR*28, and PPARA rs4253728 on sirolimus in vitro metabolism and trough concentrations in kidney transplant recipients., Clin Chem
SIROLIMUS TSC1

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Liang et al., 2010, TSC1 loss synergizes with KRAS activation in lung cancer development in the mouse and confers rapamycin sensitivity., Oncogene
SIROLIMUS IL7

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Brown et al., 2003, Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling., Proc. Natl. Acad. Sci. U.S.A.

SIROLIMUS NR1I2

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Mbatchi LC et al., 2017, Association of NR1I2, CYP3A5 and ABCB1 genetic polymorphisms with variability of temsirolimus pharmacokinetics and toxicity in patients with metastatic bladder cancer., Cancer Chemother Pharmacol

SIROLIMUS UGT1A8

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Woillard JB et al., 2010, Risk of diarrhoea in a long-term cohort of renal transplant patients given mycophenolate mofetil: the significant role of the UGT1A8 2 variant allele., Br J Clin Pharmacol

SIROLIMUS NOS1

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Aoki et al., 2006, mTOR pathway inhibition attenuates skeletal muscle growth induced by stretching., Cell Tissue Res.

SIROLIMUS ABCG2

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Pawarode et al., 2007, Differential effects of the immunosuppressive agents cyclosporin A, tacrolimus and sirolimus on drug transport by multidrug resistance proteins., Cancer Chemother. Pharmacol.

SIROLIMUS MCL1

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Wei et al., 2006, Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance., Cancer Cell

SIROLIMUS PLAU

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Dunn et al., 2001, Up-regulation of urokinase-type plasminogen activator by insulin-like growth factor-I depends upon phosphatidylinositol-3 kinase and mitogen-activated protein kinase kinase., Cancer Res.

SIROLIMUS RBL2

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Chen et al., 1996, The RB/p107/p130 phosphorylation pathway is not inhibited in rapamycin-induced G1-prolongation of NIH3T3 cells., Oncogene

SIROLIMUS DDIT3

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Entingh et al., 2001, Induction of the C/EBP homologous protein (CHOP) by amino acid deprivation requires insulin-like growth factor I, phosphatidylinositol 3-kinase, and mammalian target of rapamycin signaling., Endocrinology

SIROLIMUS BAX

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Tirado et al., 2005, Rapamycin induces apoptosis of JN-DSRCT-1 cells by increasing the Bax : Bcl-xL ratio through concurrent mechanisms dependent and independent of its mTOR inhibitory activity., Oncogene

SIROLIMUS ABCB1

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Cummins et al., 2004, CYP3A4-transfected Caco-2 cells as a tool for understanding biochemical absorption barriers: studies with sirolimus and midazolam., J. Pharmacol. Exp. Ther.

Mbatchi LC et al., 2017, Association of NR1I2, CYP3A5 and ABCB1 genetic polymorphisms with variability of temsirolimus pharmacokinetics and toxicity in patients with metastatic bladder cancer., Cancer Chemother Pharmacol

Sam WJ et al., 2012, Associations of ABCB1 and IL-10 genetic polymorphisms with sirolimus-induced dyslipidemia in renal transplant recipients., Transplantation

SIROLIMUS CTLA4

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Lai et al., 1994, CD28 signaling causes a sustained down-regulation of I kappa B alpha which can be prevented by the immunosuppressant rapamycin., J. Biol. Chem.

Vanasek et al., 2001, Antagonistic roles for CTLA-4 and the mammalian target of rapamycin in the regulation of clonal anergy: enhanced cell cycle progression promotes recall antigen responsiveness., J. Immunol.

SIROLIMUS PIM1

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Fox et al., 2005, The Pim kinases control rapamycin-resistant T cell survival and activation., J. Exp. Med.

SIROLIMUS WT1

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Tirado et al., 2005, Rapamycin induces apoptosis of JN-DSRCT-1 cells by increasing the Bax : Bcl-xL ratio through concurrent mechanisms dependent and independent of its mTOR inhibitory activity., Oncogene

SIROLIMUS PGR

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Renoir et al., 1992, [Effect of immunosuppressants FK506 and rapamycin on the function of progesterone receptor: protein "p59-HBI", intersection between immunology and endocrinology?]., C. R. Acad. Sci. III, Sci. Vie

SIROLIMUS IGFBP1

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Patel et al., 2002, Insulin regulation of hepatic insulin-like growth factor-binding protein-1 (IGFBP-1) gene expression and mammalian target of rapamycin (mTOR) signalling is impaired by the presence of hydrogen peroxide., Biochem. J.

SIROLIMUS FKBP4

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Bierer et al., 1990, Probing immunosuppressant action with a nonnatural immunophilin ligand., Science

SIROLIMUS EIF4E

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Fraser et al., 1999, The association of initiation factor 4F with poly(A)-binding protein is enhanced in serum-stimulated Xenopus kidney cells., J. Biol. Chem.

Feigenblum et al., 1996, Cap-binding protein (eukaryotic initiation factor 4E) and 4E-inactivating protein BP-1 independently regulate cap-dependent translation., Mol. Cell. Biol.

Naegele et al., 2004, Molecular cross-talk between MEK1/2 and mTOR signaling during recovery of 293 cells from hypertonic stress., J. Biol. Chem.

SIROLIMUS DDC

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Sanftner et al., 2006, Dimerizer regulation of AADC expression and behavioral response in AAV-transduced 6-OHDA lesioned rats., Mol. Ther.
SIROLIMUS MAPK10

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Duncan et al., 2005, Signal transduction pathways leading to increased eIF4E phosphorylation caused by oxidative stress., Free Radic. Biol. Med.
SIROLIMUS PRKAA1

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Hahn-Windgassen et al., 2005, Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity., J. Biol. Chem.
SIROLIMUS IL17A

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Vanaudenaerde et al., 2007, Macrolides inhibit IL17-induced IL8 and 8-isoprostane release from human airway smooth muscle cells., Am. J. Transplant.

SIROLIMUS CYP3A5

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Rodríguez-Jiménez C et al., 2017, Influence of genetic polymorphisms of CYP3A5 and ABCB1 on sirolimus pharmacokinetics, patient and graft survival and other clinical outcomes in renal transplant., Drug Metab Pers Ther

Li Y et al., 2015, CYP3A5 and ABCB1 genotype influence tacrolimus and sirolimus pharmacokinetics in renal transplant recipients., Springerplus

Emoto C et al., 2015, The impact of CYP3A5*3 polymorphism on sirolimus pharmacokinetics: insights from predictions with a physiologically-based pharmacokinetic model., Br J Clin Pharmacol

SIROLIMUS IL15

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Dubois et al., 2003, Distinct pathways involving the FK506-binding proteins 12 and 12.6 underlie IL-2-versus IL-15-mediated proliferation of T cells., Proc. Natl. Acad. Sci. U.S.A.

SIROLIMUS RPS6KB1

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Schalm et al., 2002, Identification of a conserved motif required for mTOR signaling., Curr. Biol.

Martin et al., 2001, Ribosomal S6 kinase 2 inhibition by a potent C-terminal repressor domain is relieved by mitogen-activated protein-extracellular signal-regulated kinase kinase-regulated phosphorylation., J. Biol. Chem.

Martin et al., 2001, Regulation of ribosomal S6 kinase 2 by effectors of the phosphoinositide 3-kinase pathway., J. Biol. Chem.

SIROLIMUS ERBB2

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Perera et al., 2009, HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy., Proc. Natl. Acad. Sci. U.S.A.
SIROLIMUS DCN

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Schaefer et al., 2007, Decorin-mediated regulation of fibrillin-1 in the kidney involves the insulin-like growth factor-I receptor and Mammalian target of rapamycin., Am. J. Pathol.
SIROLIMUS MMP1

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Poulalhon et al., 2006, Modulation of collagen and MMP-1 gene expression in fibroblasts by the immunosuppressive drug rapamycin. A direct role as an antifibrotic agent?, J. Biol. Chem.
SIROLIMUS ITGAL

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Poston et al., 1999, Antisense oligodeoxynucleotides prevent acute cardiac allograft rejection via a novel, nontoxic, highly efficient transfection method., Transplantation

SIROLIMUS TCF7L2

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

Ling Q et al., 2013, Association between donor and recipient TCF7L2 gene polymorphisms and the risk of new-onset diabetes mellitus after liver transplantation in a Han Chinese population., J Hepatol

Kurzawski M et al., 2011, Association of transcription factor 7-like 2 (TCF7L2) gene polymorphism with posttransplant diabetes mellitus in kidney transplant patients medicated with tacrolimus., Pharmacol Rep

SIROLIMUS OPRK1

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:
SIROLIMUS AR

Interaction Types & Directionality:

n/a

Interaction Info:

Publications:

DrugBank: DB00877

Version: 5.1.7

Alternate Names:

SIROLIMUS DrugBank Drug Name

53123-88-9 CAS Number

Gd-sirolimus Drug Brand

Drug Info:

Drug Type small molecule

Drug Groups approved

Drug Groups investigational

Publications:

Chen et al., 2002, TTD: Therapeutic Target Database., Nucleic Acids Res.

Dowling et al., 2010, Dissecting the role of mTOR: lessons from mTOR inhibitors., Biochim. Biophys. Acta

Shuuin et al., 2009, [Mammalian target of rapamycin, its mode of action and clinical response in metastatic clear cell carcinoma]., Gan To Kagaku Ryoho

MyCancerGenome: SIROLIMUS
- Version: 20-Jun-2017
Alternate Names:

AY22989 Development Name

SILA9268A Development Name

WY-090217 Development Name

Drug Info:

Drug Class Kinase Inhibitors

Notes rapalogue

Publications:
TEND: SIROLIMUS
- Version: 01-August-2011
Alternate Names:

SIROLIMUS Primary Drug Name

Drug Info:

Year of Approval 2007

Drug Class immunosuppressive agents

Publications:
TdgClinicalTrial: SIROLIMUS
- Version: January-2014
Alternate Names:

Drug Info:

Drug Indications immunosuppressant

Drug Class Small Molecule

FDA Approval approved

Publications:

DTC: SIROLIMUS

Version: 02-September-2020

Alternate Names:

CHEMBL413 ChEMBL Drug ID

Drug Info:

Publications:

Du L et al., 2014, Cytotoxic dimeric epipolythiodiketopiperazines from the ascomycetous fungus Preussia typharum., J Nat Prod

Pratt MR et al., 2007, Small-molecule-mediated rescue of protein function by an inducible proteolytic shunt., Proc Natl Acad Sci U S A

Salomé C et al., 2014, Benzofuran derivatives as anticancer inhibitors of mTOR signaling., Eur J Med Chem

NCI: RAPAMYCIN

Version: 14-September-2017

Alternate Names:

C1212 NCI drug code

Drug Info:

Publications:

Nardacci et al., 2005, Characterization of cell death pathways in human immunodeficiency virus-associated encephalitis., Am. J. Pathol.

Purdom-Dickinson et al., 2007, Translational control of nrf2 protein in activation of antioxidant response by oxidants., Mol. Pharmacol.

Wei et al., 2006, Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance., Cancer Cell

NCI: SIROLIMUS

Version: 14-September-2017

Alternate Names:

C1212 NCI drug code

Drug Info:

Publications:

Pawarode et al., 2007, Differential effects of the immunosuppressive agents cyclosporin A, tacrolimus and sirolimus on drug transport by multidrug resistance proteins., Cancer Chemother. Pharmacol.

Cummins et al., 2004, CYP3A4-transfected Caco-2 cells as a tool for understanding biochemical absorption barriers: studies with sirolimus and midazolam., J. Pharmacol. Exp. Ther.

PharmGKB: sirolimus

Version: 18-August-2020

Alternate Names:

Drug Info:

Publications:

Woillard JB et al., 2013, Effect of CYP3A422, POR28, and PPARA rs4253728 on sirolimus in vitro metabolism and trough concentrations in kidney transplant recipients., Clin Chem

Woillard JB et al., 2010, Risk of diarrhoea in a long-term cohort of renal transplant patients given mycophenolate mofetil: the significant role of the UGT1A8 2 variant allele., Br J Clin Pharmacol

Mbatchi LC et al., 2017, Association of NR1I2, CYP3A5 and ABCB1 genetic polymorphisms with variability of temsirolimus pharmacokinetics and toxicity in patients with metastatic bladder cancer., Cancer Chemother Pharmacol

DoCM: RAPAMYCIN

Version: 27-September-2017

Alternate Names:

Drug Info:

Publications:

Grabiner et al., 2014, A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity., Cancer Discov

Chang et al., 2016, Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity., Nat. Biotechnol.

DoCM: SIROLIMUS

Version: 27-September-2017

Alternate Names:

Drug Info:

Publications:

MacConaill et al., 2014, Prospective enterprise-level molecular genotyping of a cohort of cancer patients., J Mol Diagn

Ganesan et al., 2016, Epidermal Growth Factor Receptor P753S Mutation in Cutaneous Squamous Cell Carcinoma Responsive to Cetuximab-Based Therapy., J. Clin. Oncol.

Engelman et al., 2007, PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib., Cancer Res.

JAX-CKB: Sirolimus

Version: 15-September-2020

Alternate Names:

Drug Info:

Publications:

Mavrakis et al., 2008, Tumorigenic activity and therapeutic inhibition of Rheb GTPase., Genes Dev.

Gopalan PK et al., 2018, CDK4/6 inhibition stabilizes disease in patients with p16-null non-small cell lung cancer and is synergistic with mTOR inhibition., Oncotarget

Lovly et al., 2011, Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors., Cancer Res.

TALC: SIROLIMUS
- Version: 12-May-2016
Alternate Names:

SIROLIMUS Primary Drug Name

SIROLIMUS Drug Generic Name

RAPAMUNE Drug Trade Name

Drug Info:

Publications:
GuideToPharmacologyInteractions: 178102653
- Version: 20-July-2020
Alternate Names:

SIROLIMUS GuideToPharmacology Ligand Name

Drug Info:

Publications:
TTD: Sirolimus
- Version: 2020.06.01
Alternate Names:

D03LJR TTD Drug ID

Drug Info:

Publications:
TTD: Rapamycin
- Version: 2020.06.01
Alternate Names:

D0T6DK TTD Drug ID

Drug Info:

Publications:
ChemblDrugs: chembl:CHEMBL413
- Version: ChEMBL_27
Alternate Names:

Drug Info:

Publications:
ChemblInteractions: CHEMBL413
- Version: chembl_23
Alternate Names:

Drug Info:

Publications:
MyCancerGenomeClinicalTrial: RAPAMYCIN
- Version: 30-February-2014
Alternate Names:

Drug Info:

Publications:
ClearityFoundationClinicalTrial: SIROLIMUS
- Version: 15-June-2013
Alternate Names:

Drug Info:

Publications:
CGI: Sirolimus
- Version: 14-September-2020
Alternate Names:

Drug Info:

Publications:

Direct Interaction	yes
Mechanism of Interaction	FK506-binding protein 1A inhibitor
Details of the Assay for Interaction	Measuring ability to inhibit the proteins rotamase activity

Drug family	MTOR inhibitor
Alteration	MTOR:L1460P,S2215Y,R2505P
Trial Name	LCP-Siro, sirolimus

combination therapy	Sirolimus + Trametinib
Indication/Tumor Type	head and neck squamous cell carcinoma
Response Type	sensitive

Indication/Tumor Type	colon cancer
Response Type	sensitive
Approval Status	Preclinical

Indication/Tumor Type	Advanced Solid Tumor
Response Type	sensitive
Approval Status	Preclinical

Response Type	predicted – sensitive
combination therapy	Doxorubicin + Sirolimus
Evidence Type	Actionable

combination therapy	Sirolimus + X-396
Indication/Tumor Type	non-small cell lung carcinoma
Response Type	sensitive

Indication/Tumor Type	pancreatic ductal adenocarcinoma
Response Type	conflicting
Approval Status	Preclinical

Alteration	EGFR:P753S
Drug family	EGFR mAb inhibitor;MTOR inhibitor
combination therapy	Cetuximab;Sirolimus

Trial Name	LCP-Siro, sirolimus
Novel drug target	Established target

Indication/Tumor Type	retinoblastoma
Response Type	sensitive
Approval Status	Preclinical

combination therapy	AZD4547 + Sirolimus
Indication/Tumor Type	lung adenocarcinoma
Response Type	sensitive

SIROLIMUS	DrugBank Drug Name
53123-88-9	CAS Number
Gd-sirolimus	Drug Brand

AY22989	Development Name
SILA9268A	Development Name
WY-090217	Development Name

SIROLIMUS	Primary Drug Name
SIROLIMUS	Drug Generic Name
RAPAMUNE	Drug Trade Name

SIROLIMUS Drug Record

SIROLIMUS chembl:CHEMBL413 ApprovedAntineoplasticImmunotherapy

Alternate Names:

Drug Info:

Publications:

Interaction Types & Directionality: inhibitor (inhibitory)

Interaction Info: Direct Interaction yes Mechanism of Interaction FK506-binding protein 1A inhibitor Details of the Assay for Interaction Measuring ability to inhibit the proteins rotamase activity

Interaction Types & Directionality: inhibitor (inhibitory)

Interaction Info: Drug family MTOR inhibitor Alteration MTOR:L1460P,S2215Y,R2505P Trial Name LCP-Siro, sirolimus

Interaction Types & Directionality: n/a

Interaction Info: combination therapy Sirolimus + Trametinib Indication/Tumor Type head and neck squamous cell carcinoma Response Type sensitive

Publications: Yamaguchi et al., 2016, A synthetic-lethality RNAi screen reveals an ERK-mTOR co-targeting pro-apoptotic switch in PIK3CA+ oral cancers., Oncotarget

Interaction Types & Directionality: n/a

Interaction Info: Indication/Tumor Type colon cancer Response Type sensitive Approval Status Preclinical

Interaction Types & Directionality: n/a

Interaction Info: Indication/Tumor Type Advanced Solid Tumor Response Type sensitive Approval Status Preclinical

Interaction Types & Directionality: n/a

Interaction Info: Response Type predicted – sensitive combination therapy Doxorubicin + Sirolimus Evidence Type Actionable

Publications: Mavrakis et al., 2008, Tumorigenic activity and therapeutic inhibition of Rheb GTPase., Genes Dev.

Interaction Types & Directionality: n/a

Interaction Info: combination therapy Sirolimus + X-396 Indication/Tumor Type non-small cell lung carcinoma Response Type sensitive

Publications: Lovly et al., 2011, Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors., Cancer Res.

Interaction Types & Directionality: n/a

Interaction Info: Indication/Tumor Type pancreatic ductal adenocarcinoma Response Type conflicting Approval Status Preclinical

Publications: Mungamuri et al., 2006, Survival signaling by Notch1: mammalian target of rapamycin (mTOR)-dependent inhibition of p53., Cancer Res. Palm et al., 2015, The Utilization of Extracellular Proteins as Nutrients Is Suppressed by mTORC1., Cell

Interaction Types & Directionality: n/a

Interaction Info: Evidence Type Actionable Approval Status Preclinical Response Type sensitive

Interaction Types & Directionality: n/a

Interaction Info: Alteration EGFR:P753S Drug family EGFR mAb inhibitor;MTOR inhibitor combination therapy Cetuximab;Sirolimus

Interaction Types & Directionality: n/a

Interaction Info: Trial Name LCP-Siro, sirolimus Novel drug target Established target

Publications: Sehgal, 2003, Sirolimus: its discovery, biological properties, and mechanism of action., Transplant. Proc.

Interaction Types & Directionality: n/a

Interaction Info: Drug family MTOR inhibitor Alteration NF1:del Alteration NF1:.

Publications: Maertens et al., 2013, Elucidating distinct roles for NF1 in melanomagenesis., Cancer Discov

Interaction Types & Directionality: n/a

Interaction Info: Indication/Tumor Type retinoblastoma Response Type sensitive Approval Status Preclinical

Interaction Types & Directionality: n/a

Interaction Info: Indication/Tumor Type pancreatic ductal adenocarcinoma Response Type conflicting Approval Status Preclinical

Publications: Yamaguchi et al., 2016, A synthetic-lethality RNAi screen reveals an ERK-mTOR co-targeting pro-apoptotic switch in PIK3CA+ oral cancers., Oncotarget Palm et al., 2015, The Utilization of Extracellular Proteins as Nutrients Is Suppressed by mTORC1., Cell

Interaction Types & Directionality: n/a

Interaction Info: Indication/Tumor Type colon cancer Response Type sensitive Approval Status Preclinical

Interaction Types & Directionality: n/a

Interaction Info: combination therapy AZD4547 + Sirolimus Indication/Tumor Type lung adenocarcinoma Response Type sensitive

Publications: Singleton et al., 2015, Kinome RNAi Screens Reveal Synergistic Targeting of MTOR and FGFR1 Pathways for Treatment of Lung Cancer and HNSCC., Cancer Res.

Interaction Types & Directionality: n/a

Interaction Info: Evidence Type Actionable Approval Status Preclinical - Cell culture Response Type sensitive

Publications: Gopalan PK et al., 2018, CDK4/6 inhibition stabilizes disease in patients with p16-null non-small cell lung cancer and is synergistic with mTOR inhibition., Oncotarget

Interaction Types & Directionality: n/a

Interaction Info: Drug family MTOR inhibitor Alteration PTEN:del Alteration PTEN:.

Publications:

Interaction Types & Directionality: n/a

Interaction Info:

Publications: Nardacci et al., 2005, Characterization of cell death pathways in human immunodeficiency virus-associated encephalitis., Am. J. Pathol.

Interaction Types & Directionality: n/a

Interaction Info:

Publications: Purdom-Dickinson et al., 2007, Translational control of nrf2 protein in activation of antioxidant response by oxidants., Mol. Pharmacol.

Interaction Types & Directionality: n/a

Interaction Info:

Interaction Types & Directionality: n/a

Interaction Info:

Publications: Woillard JB et al., 2013, Effect of CYP3A4*22, POR*28, and PPARA rs4253728 on sirolimus in vitro metabolism and trough concentrations in kidney transplant recipients., Clin Chem

Interaction Types & Directionality: n/a

Interaction Info:

Publications: Liang et al., 2010, TSC1 loss synergizes with KRAS activation in lung cancer development in the mouse and confers rapamycin sensitivity., Oncogene

Interaction Types & Directionality: n/a

Interaction Info:

Publications: Brown et al., 2003, Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling., Proc. Natl. Acad. Sci. U.S.A.

Interaction Types & Directionality: n/a

Interaction Info:

Publications: Mbatchi LC et al., 2017, Association of NR1I2, CYP3A5 and ABCB1 genetic polymorphisms with variability of temsirolimus pharmacokinetics and toxicity in patients with metastatic bladder cancer., Cancer Chemother Pharmacol

Interaction Types & Directionality: n/a

Interaction Info:

Publications: Woillard JB et al., 2010, Risk of diarrhoea in a long-term cohort of renal transplant patients given mycophenolate mofetil: the significant role of the UGT1A8 2 variant allele., Br J Clin Pharmacol

Interaction Types & Directionality: n/a

Interaction Info:

Publications: Aoki et al., 2006, mTOR pathway inhibition attenuates skeletal muscle growth induced by stretching., Cell Tissue Res.

Interaction Types & Directionality: n/a

Interaction Info:

Publications: Pawarode et al., 2007, Differential effects of the immunosuppressive agents cyclosporin A, tacrolimus and sirolimus on drug transport by multidrug resistance proteins., Cancer Chemother. Pharmacol.

Interaction Types & Directionality:

inhibitor (inhibitory)

Interaction Info:

Direct Interaction yes

Mechanism of Interaction FK506-binding protein 1A inhibitor

Details of the Assay for Interaction Measuring ability to inhibit the proteins rotamase activity

Interaction Types & Directionality:

inhibitor (inhibitory)

Interaction Info:

Drug family MTOR inhibitor

Alteration MTOR:L1460P,S2215Y,R2505P

Trial Name LCP-Siro, sirolimus

Interaction Types & Directionality:

n/a

Interaction Info:

combination therapy Sirolimus + Trametinib

Indication/Tumor Type head and neck squamous cell carcinoma

Response Type sensitive

Publications:

Yamaguchi et al., 2016, A synthetic-lethality RNAi screen reveals an ERK-mTOR co-targeting pro-apoptotic switch in PIK3CA+ oral cancers., Oncotarget

Interaction Types & Directionality:

n/a

Interaction Info:

Indication/Tumor Type colon cancer

Response Type sensitive

Approval Status Preclinical

Interaction Types & Directionality:

n/a

Interaction Info:

Indication/Tumor Type Advanced Solid Tumor

Response Type sensitive

Approval Status Preclinical

Interaction Types & Directionality:

n/a

Interaction Info:

Response Type predicted – sensitive

combination therapy Doxorubicin + Sirolimus

Evidence Type Actionable

Publications:

Mavrakis et al., 2008, Tumorigenic activity and therapeutic inhibition of Rheb GTPase., Genes Dev.

Interaction Types & Directionality:

n/a

Interaction Info:

combination therapy Sirolimus + X-396

Indication/Tumor Type non-small cell lung carcinoma

Response Type sensitive

Publications:

Lovly et al., 2011, Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors., Cancer Res.

Interaction Types & Directionality:

n/a

Interaction Info:

Indication/Tumor Type pancreatic ductal adenocarcinoma

Response Type conflicting

Approval Status Preclinical

Publications:

Mungamuri et al., 2006, Survival signaling by Notch1: mammalian target of rapamycin (mTOR)-dependent inhibition of p53., Cancer Res.

Palm et al., 2015, The Utilization of Extracellular Proteins as Nutrients Is Suppressed by mTORC1., Cell

Interaction Types & Directionality:

n/a

Interaction Info:

Evidence Type Actionable

Approval Status Preclinical

Response Type sensitive

Interaction Types & Directionality:

n/a

Interaction Info:

Alteration EGFR:P753S

Drug family EGFR mAb inhibitor;MTOR inhibitor

combination therapy Cetuximab;Sirolimus

Interaction Types & Directionality:

n/a

Interaction Info:

Trial Name LCP-Siro, sirolimus

Novel drug target Established target

Publications:

Sehgal, 2003, Sirolimus: its discovery, biological properties, and mechanism of action., Transplant. Proc.

Interaction Types & Directionality:

n/a

Interaction Info:

Drug family MTOR inhibitor

Alteration NF1:del

Alteration NF1:.

Publications:

Maertens et al., 2013, Elucidating distinct roles for NF1 in melanomagenesis., Cancer Discov

Interaction Types & Directionality:

n/a

Interaction Info:

Indication/Tumor Type retinoblastoma

Response Type sensitive

Approval Status Preclinical

Interaction Types & Directionality:

n/a

Interaction Info:

Indication/Tumor Type pancreatic ductal adenocarcinoma

Response Type conflicting

Approval Status Preclinical

Publications:

Yamaguchi et al., 2016, A synthetic-lethality RNAi screen reveals an ERK-mTOR co-targeting pro-apoptotic switch in PIK3CA+ oral cancers., Oncotarget

Palm et al., 2015, The Utilization of Extracellular Proteins as Nutrients Is Suppressed by mTORC1., Cell

Interaction Types & Directionality:

n/a

Interaction Info:

Indication/Tumor Type colon cancer

Response Type sensitive

Approval Status Preclinical

Interaction Types & Directionality:

n/a

Interaction Info:

combination therapy AZD4547 + Sirolimus

Indication/Tumor Type lung adenocarcinoma

Response Type sensitive

Publications:

Singleton et al., 2015, Kinome RNAi Screens Reveal Synergistic Targeting of MTOR and FGFR1 Pathways for Treatment of Lung Cancer and HNSCC., Cancer Res.

Interaction Types & Directionality:

n/a

Interaction Info:

Evidence Type Actionable

Approval Status Preclinical - Cell culture

Response Type sensitive

Publications:

Gopalan PK et al., 2018, CDK4/6 inhibition stabilizes disease in patients with p16-null non-small cell lung cancer and is synergistic with mTOR inhibition., Oncotarget

Interaction Types & Directionality:

n/a

Interaction Info:

Drug family MTOR inhibitor

Alteration PTEN:del

Alteration PTEN:.

Interaction Types & Directionality:

n/a

Publications:

Nardacci et al., 2005, Characterization of cell death pathways in human immunodeficiency virus-associated encephalitis., Am. J. Pathol.

Interaction Types & Directionality:

n/a

Publications:

Purdom-Dickinson et al., 2007, Translational control of nrf2 protein in activation of antioxidant response by oxidants., Mol. Pharmacol.

Interaction Types & Directionality:

n/a

Interaction Types & Directionality:

n/a

Publications:

Woillard JB et al., 2013, Effect of CYP3A422, POR28, and PPARA rs4253728 on sirolimus in vitro metabolism and trough concentrations in kidney transplant recipients., Clin Chem

Interaction Types & Directionality:

n/a

Publications:

Liang et al., 2010, TSC1 loss synergizes with KRAS activation in lung cancer development in the mouse and confers rapamycin sensitivity., Oncogene

Interaction Types & Directionality:

n/a

Publications:

Brown et al., 2003, Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling., Proc. Natl. Acad. Sci. U.S.A.

Interaction Types & Directionality:

n/a

Publications:

Mbatchi LC et al., 2017, Association of NR1I2, CYP3A5 and ABCB1 genetic polymorphisms with variability of temsirolimus pharmacokinetics and toxicity in patients with metastatic bladder cancer., Cancer Chemother Pharmacol

Interaction Types & Directionality:

n/a

Publications:

Woillard JB et al., 2010, Risk of diarrhoea in a long-term cohort of renal transplant patients given mycophenolate mofetil: the significant role of the UGT1A8 2 variant allele., Br J Clin Pharmacol

Interaction Types & Directionality:

n/a

Publications:

Aoki et al., 2006, mTOR pathway inhibition attenuates skeletal muscle growth induced by stretching., Cell Tissue Res.

Interaction Types & Directionality:

n/a

Publications:

Pawarode et al., 2007, Differential effects of the immunosuppressive agents cyclosporin A, tacrolimus and sirolimus on drug transport by multidrug resistance proteins., Cancer Chemother. Pharmacol.

Interaction Types & Directionality:

n/a

Publications:

Wei et al., 2006, Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance., Cancer Cell

Interaction Types & Directionality:

n/a

Publications:

Dunn et al., 2001, Up-regulation of urokinase-type plasminogen activator by insulin-like growth factor-I depends upon phosphatidylinositol-3 kinase and mitogen-activated protein kinase kinase., Cancer Res.

Interaction Types & Directionality:

n/a

Publications:

Chen et al., 1996, The RB/p107/p130 phosphorylation pathway is not inhibited in rapamycin-induced G1-prolongation of NIH3T3 cells., Oncogene

Interaction Types & Directionality:

n/a

Publications:

Entingh et al., 2001, Induction of the C/EBP homologous protein (CHOP) by amino acid deprivation requires insulin-like growth factor I, phosphatidylinositol 3-kinase, and mammalian target of rapamycin signaling., Endocrinology

Interaction Types & Directionality:

n/a

Publications:

Tirado et al., 2005, Rapamycin induces apoptosis of JN-DSRCT-1 cells by increasing the Bax : Bcl-xL ratio through concurrent mechanisms dependent and independent of its mTOR inhibitory activity., Oncogene

Interaction Types & Directionality:

n/a

Interaction Types & Directionality:

n/a

Interaction Types & Directionality:

n/a

Publications:

Fox et al., 2005, The Pim kinases control rapamycin-resistant T cell survival and activation., J. Exp. Med.