Details of the Drug Combination

General Information of Drug Combination (ID: DCR5S6Y)

• Drug Combination Name: Ruxolitinib + Crizotinib
• Indication: Clear cell renal cell carcinoma; Status: Investigative [1]
• Component Drugs:
  Ruxolitinib (DM7Q98D): Small molecular drug
  Crizotinib (DM4F29C): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: CAKI-1
  Zero Interaction Potency (ZIP) Score: 0.77
  Bliss Independence Score: 2.28
  Loewe Additivity Score: 6.37
  LHighest Single Agent (HSA) Score: 6.3

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Ruxolitinib

Disease Entry	ICD 11	Status	REF
Essential thrombocythemia	3B63.1Z	Approved	[2]
High-risk myelofibrosis	2A20.2	Approved	[3]
Myelofibrosis	2A22	Approved	[4]
Myeloproliferative neoplasm	2A20	Approved	[5]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[6]
Pancreatic cancer	2C10	Phase 3	[3]
Atopic dermatitis	EA80	Phase 1/2	[7]
Vitiligo	ED63.0	Phase 1/2	[7]

Ruxolitinib Interacts with 5 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Janus kinase 2 (JAK-2)	TTRMX3V	JAK2_HUMAN	Modulator	[9]
Janus kinase 1 (JAK-1)	TT6DM01	JAK1_HUMAN	Modulator	[9]
Urokinase plasminogen activator surface receptor (PLAUR)	TTPRL03	UPAR_HUMAN	Inhibitor	[10]
HUMAN janus kinase 1 (JAK-1)	TTWKB01	JAK1_HUMAN	Inhibitor	[11]
HUMAN janus kinase 2 (JAK-2)	TT0F5HE	JAK2_HUMAN	Inhibitor	[11]

Ruxolitinib Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Mitogen-activated protein kinase 14 (MAPK14)	OT5TCO3O	MK14_HUMAN	Increases ADR	[12]

Indication(s) of Crizotinib

Disease Entry	ICD 11	Status	REF
Non-small-cell lung cancer	2C25.Y	Approved	[8]

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	[4]
ALK tyrosine kinase receptor (ALK)	TTPMQSO	ALK_HUMAN	Modulator	[4]
Proto-oncogene c-Ros (ROS1)	TTSZ6Y3	ROS1_HUMAN	Modulator	[4]
HGF/Met signaling pathway (HGF/Met pathway)	TTKA5LP	NOUNIPROTAC	Inhibitor	[16]

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	[17]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[18]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[18]

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	[19]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[19]

Crizotinib Interacts with 24 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Activity	[20]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Response To Substance	[14]
CD44 antigen (CD44)	OT9TTJ41	CD44_HUMAN	Decreases Expression	[13]
Epithelial cell adhesion molecule (EPCAM)	OTHBZK5X	EPCAM_HUMAN	Decreases Expression	[13]
Insulin-induced gene 1 protein (INSIG1)	OTZF5X1D	INSI1_HUMAN	Increases Expression	[21]
Hydroxymethylglutaryl-CoA synthase, cytoplasmic (HMGCS1)	OTCO26FV	HMCS1_HUMAN	Increases Expression	[21]
Sterol regulatory element-binding protein 2 (SREBF2)	OTBXUNPL	SRBP2_HUMAN	Increases Expression	[21]
Acetyl-CoA carboxylase 1 (ACACA)	OT5CQPZY	ACACA_HUMAN	Increases Phosphorylation	[21]
Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C)	OT6KFNMS	CAC1C_HUMAN	Decreases Activity	[21]
Sodium channel protein type 5 subunit alpha (SCN5A)	OTGYZWR6	SCN5A_HUMAN	Decreases Activity	[21]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[14]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[14]
Follitropin subunit beta (FSHB)	OTGLS283	FSHB_HUMAN	Decreases Secretion	[22]
Lutropin subunit beta (LHB)	OT5GBOVJ	LSHB_HUMAN	Decreases Secretion	[22]
Tyrosine-protein kinase Lck (LCK)	OT883FG9	LCK_HUMAN	Decreases Activity	[23]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[24]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[24]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[25]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[25]
Ras GTPase-activating-like protein IQGAP1 (IQGAP1)	OTZRWTGA	IQGA1_HUMAN	Decreases Phosphorylation	[26]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Phosphorylation	[27]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Expression	[14]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Decreases Activity	[20]
Mast/stem cell growth factor receptor Kit (KIT)	OTHUY3VZ	KIT_HUMAN	Decreases Response To Substance	[28]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Astrocytoma	DC36MUF	U251	Investigative	[1]
Invasive ductal carcinoma	DCW3TCL	BT-549	Investigative	[29]
Invasive ductal carcinoma	DCG6BZ6	HS 578T	Investigative	[29]
Melanoma	DCYBIBH	UACC-257	Investigative	[30]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [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: 5688).
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Ruxolitinib FDA Label
• [6] Incyte begins Phase III trial of ruxolitinib to treat Covid-19. 20.April.2020.
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] 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).
• [9] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [10] Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis.Cell Cycle. 2014;13(12):1958-69.
• [11] The Use of Anti-Inflammatory Drugs in the Treatment of People With Severe Coronavirus Disease 2019 (COVID-19): The Perspectives of Clinical Immunologists From China. Clin Immunol. 2020 May;214:108393.
• [12] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [13] Enhancement of the antiproliferative activity of gemcitabine by modulation of c-Met pathway in pancreatic cancer. Curr Pharm Des. 2013;19(5):940-50.
• [14] 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.
• [15] 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.
• [16] Met tyrosine kinase inhibitor, PF-2341066, suppresses growth and invasion of nasopharyngeal carcinoma.Drug Des Devel Ther. 2015 Aug 26;9:4897-907.
• [17] 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.
• [18] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [19] Crizotinib for the treatment of non-small-cell lung cancer. Am J Health Syst Pharm. 2013 Jun 1;70(11):943-7.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1126165
• [30] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125976