Details of the Drug Combination

General Information of Drug Combination (ID: DCWT0SC)

• Drug Combination Name: Nevirapine + Ruxolitinib
• Indication: Hodgkin lymphoma; Status: Investigative [1]
• Component Drugs:
  Nevirapine (DM6HX9B): Small molecular drug
  Ruxolitinib (DM7Q98D): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: L-1236
  Zero Interaction Potency (ZIP) Score: 11.52
  Bliss Independence Score: 11.87
  Loewe Additivity Score: 10.44
  LHighest Single Agent (HSA) Score: 12.87

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Nevirapine

Disease Entry	ICD 11	Status	REF
Human immunodeficiency virus infection	1C62	Approved	[2]

Nevirapine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human immunodeficiency virus Reverse transcriptase (HIV RT)	TT84ETX	POL_HV1B1	Modulator	[11]

Nevirapine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[12]

Nevirapine Interacts with 7 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[13]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[14]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[13]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[14]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[15]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[16]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[17]

Nevirapine Interacts with 38 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Affects Binding	[18]
Sterol carrier protein 2 (SCP2)	OTPAFCPQ	SCP2_HUMAN	Increases Expression	[19]
MHC class II transactivator (CIITA)	OTRJNZFO	C2TA_HUMAN	Increases Expression	[19]
Protein NLRC5 (NLRC5)	OTY8X6MC	NLRC5_HUMAN	Increases Expression	[19]
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[20]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Expression	[9]
Pro-epidermal growth factor (EGF)	OTANRJ0L	EGF_HUMAN	Decreases Expression	[9]
Thyroglobulin (TG)	OT3ELHIJ	THYG_HUMAN	Increases Expression	[21]
Interferon gamma (IFNG)	OTXG9JM7	IFNG_HUMAN	Increases Expression	[22]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[20]
Apolipoprotein A-I (APOA1)	OT5THARI	APOA1_HUMAN	Increases Expression	[23]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[24]
Phosphatidylcholine-sterol acyltransferase (LCAT)	OTRLMLK0	LCAT_HUMAN	Increases Expression	[23]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Secretion	[25]
Keratin, type I cytoskeletal 18 (KRT18)	OTVLQFIP	K1C18_HUMAN	Increases Expression	[9]
Lipoprotein lipase (LPL)	OTTW0267	LIPL_HUMAN	Increases Expression	[25]
Thyroid peroxidase (TPO)	OTJJLL20	PERT_HUMAN	Increases Expression	[21]
Prostate-specific antigen (KLK3)	OTFGSBFJ	KLK3_HUMAN	Increases Expression	[9]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[20]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[20]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Increases Expression	[9]
Cholesteryl ester transfer protein (CETP)	OTAGPPOE	CETP_HUMAN	Increases Expression	[23]
Hepatocyte growth factor (HGF)	OTGHUA23	HGF_HUMAN	Decreases Secretion	[25]
Thyrotropin receptor (TSHR)	OT0BC8LB	TSHR_HUMAN	Increases Expression	[21]
Bone morphogenetic protein 6 (BMP6)	OT9WN536	BMP6_HUMAN	Increases Expression	[20]
Sterol regulatory element-binding protein 1 (SREBF1)	OTWBRPAI	SRBP1_HUMAN	Increases Expression	[25]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Increases Expression	[25]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Increases Expression	[25]
CCAAT/enhancer-binding protein alpha (CEBPA)	OTOM9OE4	CEBPA_HUMAN	Increases Expression	[25]
Tumor necrosis factor-inducible gene 6 protein (TNFAIP6)	OT1SLUZH	TSG6_HUMAN	Increases Expression	[20]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Increases Expression	[20]
Adiponectin (ADIPOQ)	OTNX23LE	ADIPO_HUMAN	Increases Expression	[25]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[20]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Increases Expression	[20]
Glutathione S-transferase A1 (GSTA1)	OTA7K5XA	GSTA1_HUMAN	Increases Glutathionylation	[26]
Glutathione S-transferase A3 (GSTA3)	OTJ3REE3	GSTA3_HUMAN	Increases Glutathionylation	[26]
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Increases Glutathionylation	[26]
Glutathione S-transferase Mu 1 (GSTM1)	OTSBF2MO	GSTM1_HUMAN	Increases Glutathionylation	[26]

Indication(s) of Ruxolitinib

Disease Entry	ICD 11	Status	REF
Essential thrombocythemia	3B63.1Z	Approved	[3]
High-risk myelofibrosis	2A20.2	Approved	[4]
Myelofibrosis	2A22	Approved	[5]
Myeloproliferative neoplasm	2A20	Approved	[6]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[7]
Pancreatic cancer	2C10	Phase 3	[4]
Atopic dermatitis	EA80	Phase 1/2	[8]
Vitiligo	ED63.0	Phase 1/2	[8]

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	[27]
Janus kinase 1 (JAK-1)	TT6DM01	JAK1_HUMAN	Modulator	[27]
Urokinase plasminogen activator surface receptor (PLAUR)	TTPRL03	UPAR_HUMAN	Inhibitor	[28]
HUMAN janus kinase 1 (JAK-1)	TTWKB01	JAK1_HUMAN	Inhibitor	[29]
HUMAN janus kinase 2 (JAK-2)	TT0F5HE	JAK2_HUMAN	Inhibitor	[29]

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	[30]

References

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• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] 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).
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [6] Ruxolitinib FDA Label
• [7] Incyte begins Phase III trial of ruxolitinib to treat Covid-19. 20.April.2020.
• [8] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
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• [12] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
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• [15] Helices F-G are important for the substrate specificities of CYP3A7. Drug Metab Dispos. 2007 Mar;35(3):484-92.
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• [17] RAT CYP3A and CYP2B1/2 were not associated with nevirapine-induced hepatotoxicity. Methods Find Exp Clin Pharmacol. 2006 Sep;28(7):423-31.
• [18] Bioactivation of nevirapine to a reactive quinone methide: implications for liver injury. Chem Res Toxicol. 2012 Aug 20;25(8):1708-19. doi: 10.1021/tx300172s. Epub 2012 Jul 26.
• [19] Transcriptional profiling suggests that Nevirapine and Ritonavir cause drug induced liver injury through distinct mechanisms in primary human hepatocytes. Chem Biol Interact. 2016 Aug 5;255:31-44.
• [20] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [21] Reverse transcriptase inhibitors down-regulate cell proliferation in vitro and in vivo and restore thyrotropin signaling and iodine uptake in human thyroid anaplastic carcinoma. J Clin Endocrinol Metab. 2005 Oct;90(10):5663-71. doi: 10.1210/jc.2005-0367. Epub 2005 Jul 19.
• [22] Identification of danger signals in nevirapine-induced skin rash. Chem Res Toxicol. 2013 Sep 16;26(9):1378-83. doi: 10.1021/tx400232s. Epub 2013 Aug 30.
• [23] Nevirapine increases high-density lipoprotein cholesterol concentration by stimulation of apolipoprotein A-I production. Arterioscler Thromb Vasc Biol. 2009 Sep;29(9):1336-41. doi: 10.1161/ATVBAHA.109.192088. Epub 2009 Aug 10.
• [24] Binding of anti-HIV drugs to human serum albumin. IUBMB Life. 2004 Oct;56(10):609-14. doi: 10.1080/15216540400016286.
• [25] Effects of nevirapine and efavirenz on human adipocyte differentiation, gene expression, and release of adipokines and cytokines. Antiviral Res. 2011 Aug;91(2):112-9. doi: 10.1016/j.antiviral.2011.04.018. Epub 2011 May 17.
• [26] Different Reactive Metabolites of Nevirapine Require Distinct Glutathione S-Transferase Isoforms for Bioinactivation. Chem Res Toxicol. 2016 Dec 19;29(12):2136-2144. doi: 10.1021/acs.chemrestox.6b00250. Epub 2016 Nov 28.
• [27] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [28] Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis.Cell Cycle. 2014;13(12):1958-69.
• [29] 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.
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