Details of the Drug Combination

General Information of Drug Combination (ID: DCO22EP)

• Drug Combination Name: Ruxolitinib + Raloxifene
• Indication: Pleural epithelioid mesothelioma; Status: Investigative [1]
• Component Drugs:
  Ruxolitinib (DM7Q98D): Small molecular drug
  Raloxifene (DMDKF3M): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: NCI-H226
  Zero Interaction Potency (ZIP) Score: 1.59
  Bliss Independence Score: 8.9
  Loewe Additivity Score: 4.23
  LHighest Single Agent (HSA) Score: 5.08

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	[8]
Janus kinase 1 (JAK-1)	TT6DM01	JAK1_HUMAN	Modulator	[8]
Urokinase plasminogen activator surface receptor (PLAUR)	TTPRL03	UPAR_HUMAN	Inhibitor	[9]
HUMAN janus kinase 1 (JAK-1)	TTWKB01	JAK1_HUMAN	Inhibitor	[10]
HUMAN janus kinase 2 (JAK-2)	TT0F5HE	JAK2_HUMAN	Inhibitor	[10]

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	[11]

Indication(s) of Raloxifene

Disease Entry	ICD 11	Status	REF
Osteoporosis	FB83.0	Approved	[4]

Raloxifene Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Estrogen receptor (ESR)	TTZAYWL	ESR1_HUMAN	Modulator	[12]

Raloxifene Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[13]

Raloxifene Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[14]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[15]
UDP-glucuronosyltransferase 1A10 (UGT1A10)	DEL5N6Y	UD110_HUMAN	Metabolism	[16]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult acute myeloid leukemia	DCOTO11	HL-60(TB)	Investigative	[17]
Astrocytoma	DCTP4ZN	SNB-19	Investigative	[17]
Childhood T acute lymphoblastic leukemia	DCOBSOR	CCRF-CEM	Investigative	[17]
Chronic myelogenous leukemia	DCZROOJ	K-562	Investigative	[17]
Clear cell renal cell carcinoma	DCHFQ5Q	TK-10	Investigative	[17]
Clear cell renal cell carcinoma	DCH922I	786-0	Investigative	[17]
Glioma	DCGT9LJ	SF-268	Investigative	[17]
Plasma cell myeloma	DCR0R09	RPMI-8226	Investigative	[17]
Breast adenocarcinoma	DCXKYX3	MDA-MB-468	Investigative	[18]
Carcinoma	DC0HZ18	MCF7	Investigative	[18]
Colon adenocarcinoma	DCT2VYQ	COLO 205	Investigative	[18]
Invasive ductal carcinoma	DC2G93W	HS 578T	Investigative	[18]
Invasive ductal carcinoma	DCFWM6F	T-47D	Investigative	[18]
Invasive ductal carcinoma	DCIZZ0L	BT-549	Investigative	[18]
Adenocarcinoma	DC11GQL	DU-145	Investigative	[1]
Adenocarcinoma	DCPJTY0	NCIH23	Investigative	[1]
Adenocarcinoma	DC51BJE	HCT-15	Investigative	[1]
Adenocarcinoma	DC69E61	HCT116	Investigative	[1]
Adenocarcinoma	DCUUP3Q	HT29	Investigative	[1]
Amelanotic melanoma	DCLF6EQ	M14	Investigative	[1]
Amelanotic melanoma	DCYYI57	MDA-MB-435	Investigative	[1]
Cutaneous melanoma	DCQPWGD	SK-MEL-28	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCTGWFL	OVCAR-5	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCSY3J1	OVCAR-8	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCSB9M1	NCI\\/ADR-RES	Investigative	[1]
Large cell lung carcinoma	DC9E9UT	NCI-H460	Investigative	[1]
Lung adenocarcinoma	DCB3RQ8	HOP-62	Investigative	[1]
Melanoma	DCWGVPY	SK-MEL-2	Investigative	[1]
Melanoma	DCP7V3S	UACC-257	Investigative	[1]
Minimally invasive lung adenocarcinoma	DCQEJ1M	NCI-H322M	Investigative	[1]

References

• [1] Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy.Hum Genet. 2018 Apr;137(4):293-303. doi: 10.1007/s00439-018-1882-3. Epub 2018 Apr 24.
• [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] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [9] Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis.Cell Cycle. 2014;13(12):1958-69.
• [10] 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.
• [11] 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.
• [12] 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. (Target id: 620).
• [13] Influence of hepatic and intestinal efflux transporters and their genetic variants on the pharmacokinetics and pharmacodynamics of raloxifene in osteoporosis treatment. Transl Res. 2012 Oct;160(4):298-308.
• [14] The role of P-glycoprotein in the bioactivation of raloxifene. Drug Metab Dispos. 2006 Dec;34(12):2073-8.
• [15] Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004 Nov;32(11):1201-8.
• [16] Characterization of raloxifene glucuronidation: potential role of UGT1A8 genotype on raloxifene metabolism in vivo. Cancer Prev Res (Phila). 2013 Jul;6(7):719-30.
• [17] 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.
• [18] Biologically active neutrophil chemokine pattern in tonsillitis.Clin Exp Immunol. 2004 Mar;135(3):511-8. doi: 10.1111/j.1365-2249.2003.02390.x.