General Information of Drug Combination (ID: DCRQ15A)

Drug Combination Name
Crizotinib Ixabepilone
Indication
Disease Entry Status REF
Invasive ductal carcinoma Investigative [1]
Component Drugs Crizotinib   DM4F29C Ixabepilone   DM2OZ3G
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL
High-throughput Screening Result Testing Cell Line: T-47D
Zero Interaction Potency (ZIP) Score: 1.94
Bliss Independence Score: 6.59
Loewe Additivity Score: 2.82
LHighest Single Agent (HSA) Score: 4.91

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of Crizotinib
Disease Entry ICD 11 Status REF
Non-small-cell lung cancer 2C25.Y Approved [2]
Crizotinib Interacts with 4 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Proto-oncogene c-Met (MET) TTNDSF4 MET_HUMAN Modulator [8]
ALK tyrosine kinase receptor (ALK) TTPMQSO ALK_HUMAN Modulator [8]
Proto-oncogene c-Ros (ROS1) TTSZ6Y3 ROS1_HUMAN Modulator [8]
HGF/Met signaling pathway (HGF/Met pathway) TTKA5LP NOUNIPROTAC Inhibitor [9]
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Crizotinib Interacts with 3 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
P-glycoprotein 1 (ABCB1) DTUGYRD MDR1_HUMAN Substrate [10]
Organic anion transporting polypeptide 1B1 (SLCO1B1) DT3D8F0 SO1B1_HUMAN Substrate [11]
Organic anion transporting polypeptide 1B3 (SLCO1B3) DT9C1TS SO1B3_HUMAN Substrate [11]
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Crizotinib Interacts with 2 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Metabolism [12]
Cytochrome P450 3A5 (CYP3A5) DEIBDNY CP3A5_HUMAN Metabolism [12]
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Crizotinib Interacts with 45 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) OTQGYY83 CP3A4_HUMAN Increases Expression [13]
ATP-dependent translocase ABCB1 (ABCB1) OTEJROBO MDR1_HUMAN Decreases Activity [14]
Hepatocyte growth factor receptor (MET) OT7K55MU MET_HUMAN Increases Response To Substance [6]
ALK tyrosine kinase receptor (ALK) OTV3P4V8 ALK_HUMAN Decreases Response To Substance [15]
Prominin-1 (PROM1) OTBHV8NX PROM1_HUMAN Decreases Expression [5]
CD44 antigen (CD44) OT9TTJ41 CD44_HUMAN Decreases Expression [5]
Epithelial cell adhesion molecule (EPCAM) OTHBZK5X EPCAM_HUMAN Decreases Expression [5]
Cytidine deaminase (CDA) OT3HXP6N CDD_HUMAN Decreases Expression [5]
Insulin-induced gene 1 protein (INSIG1) OTZF5X1D INSI1_HUMAN Increases Expression [16]
Acyl-CoA 6-desaturase (FADS2) OTUX531P FADS2_HUMAN Increases Expression [16]
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) OTRT3F3U HMDH_HUMAN Increases Expression [16]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Activity [16]
Fatty acid synthase (FASN) OTFII9KG FAS_HUMAN Increases Expression [16]
Caspase-7 (CASP7) OTAPJ040 CASP7_HUMAN Increases Activity [16]
Hydroxymethylglutaryl-CoA synthase, cytoplasmic (HMGCS1) OTCO26FV HMCS1_HUMAN Increases Expression [16]
Sterol regulatory element-binding protein 2 (SREBF2) OTBXUNPL SRBP2_HUMAN Increases Expression [16]
Potassium voltage-gated channel subfamily H member 2 (KCNH2) OTZX881H KCNH2_HUMAN Decreases Activity [16]
Acetyl-CoA carboxylase 1 (ACACA) OT5CQPZY ACACA_HUMAN Increases Phosphorylation [16]
Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C) OT6KFNMS CAC1C_HUMAN Decreases Activity [16]
Sodium channel protein type 5 subunit alpha (SCN5A) OTGYZWR6 SCN5A_HUMAN Decreases Activity [16]
Baculoviral IAP repeat-containing protein 5 (BIRC5) OTILXZYL BIRC5_HUMAN Decreases Expression [6]
Bcl-2-like protein 11 (BCL2L11) OTNQQWFJ B2L11_HUMAN Increases Expression [6]
Follitropin subunit beta (FSHB) OTGLS283 FSHB_HUMAN Decreases Secretion [17]
Lutropin subunit beta (LHB) OT5GBOVJ LSHB_HUMAN Decreases Secretion [17]
Tyrosine-protein kinase Lck (LCK) OT883FG9 LCK_HUMAN Decreases Activity [18]
Poly polymerase 1 (PARP1) OT310QSG PARP1_HUMAN Increases Cleavage [19]
Tissue factor (F3) OT3MSU3B TF_HUMAN Increases Expression [20]
Histone H2AX (H2AX) OT18UX57 H2AX_HUMAN Increases Phosphorylation [19]
Alanine aminotransferase 1 (GPT) OTOXOA0Q ALAT1_HUMAN Increases Secretion [21]
Mitogen-activated protein kinase 3 (MAPK3) OTCYKGKO MK03_HUMAN Decreases Phosphorylation [22]
Mitogen-activated protein kinase 1 (MAPK1) OTH85PI5 MK01_HUMAN Decreases Phosphorylation [22]
RAC-alpha serine/threonine-protein kinase (AKT1) OT8H2YY7 AKT1_HUMAN Decreases Phosphorylation [23]
Signal transducer and activator of transcription 3 (STAT3) OTAAGKYZ STAT3_HUMAN Decreases Phosphorylation [24]
Ras GTPase-activating-like protein IQGAP1 (IQGAP1) OTZRWTGA IQGA1_HUMAN Decreases Phosphorylation [25]
Small ribosomal subunit protein eS6 (RPS6) OTT4D1LN RS6_HUMAN Decreases Phosphorylation [24]
Baculoviral IAP repeat-containing protein 2 (BIRC2) OTFXFREP BIRC2_HUMAN Decreases Expression [6]
Caspase-8 (CASP8) OTA8TVI8 CASP8_HUMAN Increases Cleavage [26]
Echinoderm microtubule-associated protein-like 4 (EML4) OTJC45TA EMAL4_HUMAN Increases Mutagenesis [22]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2) OTW8V2V1 ABCG2_HUMAN Decreases Activity [14]
GTPase KRas (KRAS) OT78QCN8 RASK_HUMAN Decreases Response To Substance [27]
Pro-epidermal growth factor (EGF) OTANRJ0L EGF_HUMAN Decreases Response To Substance [23]
Epidermal growth factor receptor (EGFR) OTAPLO1S EGFR_HUMAN Decreases Response To Substance [27]
Mast/stem cell growth factor receptor Kit (KIT) OTHUY3VZ KIT_HUMAN Decreases Response To Substance [15]
Proheparin-binding EGF-like growth factor (HBEGF) OTLU00JS HBEGF_HUMAN Decreases Response To Substance [23]
Protransforming growth factor alpha (TGFA) OTPD1LL9 TGFA_HUMAN Decreases Response To Substance [23]
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⏷ Show the Full List of 45 DOT(s)
Indication(s) of Ixabepilone
Disease Entry ICD 11 Status REF
Breast cancer 2C60-2C65 Approved [3]
Breast carcinoma N.A. Approved [4]
Ixabepilone Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Tubulin (TUB) TTML2WA NOUNIPROTAC Stablizer [28]
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Ixabepilone Interacts with 1 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
P-glycoprotein 1 (ABCB1) DTUGYRD MDR1_HUMAN Substrate [29]
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Ixabepilone Interacts with 1 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Metabolism [30]
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Test Results of This Drug Combination in Other Disease Systems

Indication DrugCom ID Cell Line Status REF
Adult acute myeloid leukemia DCQJCZ2 HL-60(TB) Investigative [31]
Chronic myelogenous leukemia DCO4DKK K-562 Investigative [31]
Clear cell renal cell carcinoma DC4Y55I TK-10 Investigative [31]
Clear cell renal cell carcinoma DCES29K CAKI-1 Investigative [31]
Lung adenocarcinoma DCO5XHI MDA-MB-231 Investigative [31]
Breast adenocarcinoma DCGEGDT MDA-MB-468 Investigative [1]
Carcinoma DCK8KWX MCF7 Investigative [1]
Colon carcinoma DCU7UID KM12 Investigative [1]
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⏷ Show the Full List of 8 DrugCom(s)

References

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2 URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4903).
3 URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6824).
4 Ixabepilone FDA Label
5 Enhancement of the antiproliferative activity of gemcitabine by modulation of c-Met pathway in pancreatic cancer. Curr Pharm Des. 2013;19(5):940-50.
6 Antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer positive for MET amplification. Mol Cancer Ther. 2012 Jul;11(7):1557-64. doi: 10.1158/1535-7163.MCT-11-0934. Epub 2012 Jun 22.
7 Aberrant expression of the transcriptional factor Twist1 promotes invasiveness in ALK-positive anaplastic large cell lymphoma. Cell Signal. 2012 Apr;24(4):852-8. doi: 10.1016/j.cellsig.2011.11.020. Epub 2011 Dec 8.
8 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
9 Met tyrosine kinase inhibitor, PF-2341066, suppresses growth and invasion of nasopharyngeal carcinoma.Drug Des Devel Ther. 2015 Aug 26;9:4897-907.
10 Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar. Int J Cancer. 2014 Mar 15;134(6):1484-94.
11 Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
12 Crizotinib for the treatment of non-small-cell lung cancer. Am J Health Syst Pharm. 2013 Jun 1;70(11):943-7.
13 Prediction of crizotinib-midazolam interaction using the Simcyp population-based simulator: comparison of CYP3A time-dependent inhibition between human liver microsomes versus hepatocytes. Drug Metab Dispos. 2013 Feb;41(2):343-52.
14 Editor's Highlight: PlacentalDisposition and Effects of Crizotinib: An Ex Vivo Study in the Isolated Dual-Side Perfused Human Cotyledon. Toxicol Sci. 2017 Jun 1;157(2):500-509. doi: 10.1093/toxsci/kfx063.
15 Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med. 2012 Feb 8;4(120):120ra17. doi: 10.1126/scitranslmed.3003316. Epub 2012 Jan 25.
16 Multi-parameter in vitro toxicity testing of crizotinib, sunitinib, erlotinib, and nilotinib in human cardiomyocytes. Toxicol Appl Pharmacol. 2013 Oct 1;272(1):245-55.
17 Rapid-onset hypogonadism secondary to crizotinib use in men with metastatic nonsmall cell lung cancer. Cancer. 2012 Nov 1;118(21):5302-9. doi: 10.1002/cncr.27450. Epub 2012 Apr 4.
18 Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem. 2011 Sep 22;54(18):6342-63. doi: 10.1021/jm2007613. Epub 2011 Aug 18.
19 ROS-dependent DNA damage contributes to crizotinib-induced hepatotoxicity via the apoptotic pathway. Toxicol Appl Pharmacol. 2019 Nov 15;383:114768. doi: 10.1016/j.taap.2019.114768. Epub 2019 Oct 19.
20 Elucidating mechanisms of toxicity using phenotypic data from primary human cell systems--a chemical biology approach for thrombosis-related side effects. Int J Mol Sci. 2015 Jan 5;16(1):1008-29. doi: 10.3390/ijms16011008.
21 Cytotoxicity of 34 FDA approved small-molecule kinase inhibitors in primary rat and human hepatocytes. Toxicol Lett. 2018 Jul;291:138-148. doi: 10.1016/j.toxlet.2018.04.010. Epub 2018 Apr 12.
22 Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A. 2011 May 3;108(18):7535-40. doi: 10.1073/pnas.1019559108. Epub 2011 Apr 18.
23 Paracrine receptor activation by microenvironment triggers bypass survival signals and ALK inhibitor resistance in EML4-ALK lung cancer cells. Clin Cancer Res. 2012 Jul 1;18(13):3592-602. doi: 10.1158/1078-0432.CCR-11-2972. Epub 2012 May 2.
24 Crizotinib-resistant mutants of EML4-ALK identified through an accelerated mutagenesis screen. Chem Biol Drug Des. 2011 Dec;78(6):999-1005. doi: 10.1111/j.1747-0285.2011.01239.x. Epub 2011 Oct 31.
25 Tyrosine phosphorylation of the scaffold protein IQGAP1 in the MET pathway alters function. J Biol Chem. 2020 Dec 25;295(52):18105-18121. doi: 10.1074/jbc.RA120.015891. Epub 2020 Oct 21.
26 Keratinocytes apoptosis contributes to crizotinib induced-erythroderma. Toxicol Lett. 2020 Feb 1;319:102-110. doi: 10.1016/j.toxlet.2019.11.007. Epub 2019 Nov 7.
27 Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012 Mar 1;18(5):1472-82. doi: 10.1158/1078-0432.CCR-11-2906. Epub 2012 Jan 10.
28 Mullard A: 2010 FDA drug approvals. Nat Rev Drug Discov. 2011 Feb;10(2):82-5.
29 Ixabepilone, a novel microtubule-targeting agent for breast cancer, is a substrate for P-glycoprotein (P-gp/MDR1/ABCB1) but not breast cancer resistance protein (BCRP/ABCG2). J Pharmacol Exp Ther. 2011 May;337(2):423-32.
30 The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone: a first in class epothilone B analogue in late-phase clinical development. Clin Cancer Res. 2008 May 1;14(9):2701-9.
31 Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.