Details of the Drug Combination

General Information of Drug Combination (ID: DCMRWDA)

• Drug Combination Name: Vemurafenib + Isoniazid
• Indication: Prostate carcinoma; Status: Investigative [1]
• Component Drugs:
  Vemurafenib (DM62UG5): Small molecular drug
  Isoniazid (DM5JVS3): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: PC-3
  Zero Interaction Potency (ZIP) Score: 0.81
  Bliss Independence Score: 5.27
  Loewe Additivity Score: 4.96
  LHighest Single Agent (HSA) Score: 3.25

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Vemurafenib

Disease Entry	ICD 11	Status	REF
Melanoma	2C30	Approved	[2]

Vemurafenib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase B-raf (BRAF)	TTWCGQT	BRAF_HUMAN	Modulator	[7]

Vemurafenib Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[8]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[9]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[9]

Vemurafenib Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]

Vemurafenib Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Microphthalmia-associated transcription factor (MITF)	OT6XJCZH	MITF_HUMAN	Affects Expression	[5]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[11]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[12]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[6]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[6]
CD70 antigen (CD70)	OTHB2AL1	CD70_HUMAN	Decreases Expression	[13]
Melanocyte protein PMEL (PMEL)	OTCDDHHM	PMEL_HUMAN	Increases Expression	[5]
Melanoma antigen recognized by T-cells 1 (MLANA)	OT1N2S2K	MAR1_HUMAN	Increases Expression	[5]

Indication(s) of Isoniazid

Disease Entry	ICD 11	Status	REF
Latent tuberculosis infection	N.A.	Approved	[3]
Pulmonary tuberculosis	1B10.Z	Approved	[3]
Tuberculosis	1B10-1B1Z	Approved	[4]

Isoniazid Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial Fatty acid synthetase I (Bact inhA)	TTVTX4N	INHA_MYCTU	Inhibitor	[15]

Isoniazid Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[16]
Catalase-peroxidase (katG)	DEAGY5M	KATG_SYNE7	Metabolism	[17]
Arylamine N-acetyltransferase (NAT)	DEXCQTM	A0A3P8LE58_TSUPA	Metabolism	[18]

Isoniazid Interacts with 28 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
N-alpha-acetyltransferase 20 (NAA20)	OTJB0VA6	NAA20_HUMAN	Increases ADR	[19]
Nuclear protein 1 (NUPR1)	OT4FU8C0	NUPR1_HUMAN	Increases Expression	[20]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Increases Expression	[20]
Protein DEPP1 (DEPP1)	OTB36PHJ	DEPP1_HUMAN	Increases Expression	[20]
Aldo-keto reductase family 1 member B10 (AKR1B10)	OTOA4HTH	AK1BA_HUMAN	Increases Expression	[14]
Interleukin-12 subunit alpha (IL12A)	OTDQT8GI	IL12A_HUMAN	Increases Secretion	[14]
Interleukin-12 subunit beta (IL12B)	OT0JF8A3	IL12B_HUMAN	Increases Secretion	[14]
Sulfiredoxin-1 (SRXN1)	OTYDBO4L	SRXN1_HUMAN	Increases Expression	[14]
Gamma-butyrobetaine dioxygenase (BBOX1)	OTKEX4RK	BODG_HUMAN	Increases Expression	[21]
Sodium/potassium-transporting ATPase subunit beta-1 (ATP1B1)	OTTO6ZP4	AT1B1_HUMAN	Increases Expression	[21]
Amyloid-beta precursor protein (APP)	OTKFD7R4	A4_HUMAN	Increases Expression	[21]
14-3-3 protein sigma (SFN)	OTLJCZ1U	1433S_HUMAN	Decreases Expression	[21]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Decreases Expression	[21]
Claudin-2 (CLDN2)	OTRF3D6Y	CLD2_HUMAN	Increases Expression	[21]
Large neutral amino acids transporter small subunit 1 (SLC7A5)	OT2WPVXD	LAT1_HUMAN	Decreases Expression	[21]
Tribbles homolog 3 (TRIB3)	OTG5OS7X	TRIB3_HUMAN	Increases Expression	[21]
Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2)	OTKOZRZP	PLOD2_HUMAN	Increases Expression	[22]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[23]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[24]
5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1)	OTQY6ZSF	HEM1_HUMAN	Increases Expression	[25]
Ferrochelatase, mitochondrial (FECH)	OTDWEI6C	HEMH_HUMAN	Decreases Expression	[25]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[26]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[26]
Nuclear respiratory factor 1 (NRF1)	OTOXWNV8	NRF1_HUMAN	Decreases Expression	[27]
Natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1)	OT15YWU7	NR3L1_HUMAN	Increases Expression	[28]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[24]
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A)	OTHCDQ22	PRGC1_HUMAN	Decreases Expression	[27]
Arylamine N-acetyltransferase 2 (NAT2)	OTBPDQOY	ARY2_HUMAN	Decreases Acetylation	[29]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Carcinoma	DC52GNO	MCF7	Investigative	[30]
Colon carcinoma	DCWEDQC	KM12	Investigative	[30]
Invasive ductal carcinoma	DCYIF6I	BT-549	Investigative	[30]
Adenocarcinoma	DCSWD66	DU-145	Investigative	[1]
Adenocarcinoma	DCYK8VN	OVCAR3	Investigative	[1]
Adult T acute lymphoblastic leukemia	DCQ8L2Z	MOLT-4	Investigative	[1]
Astrocytoma	DCYHZSK	SNB-19	Investigative	[1]
Glioblastoma	DCI4L74	SNB-75	Investigative	[1]
Glioma	DCBPQ9F	SF-268	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCZZTRP	OVCAR-4	Investigative	[1]
High grade ovarian serous adenocarcinoma	DC07G84	NCI\\/ADR-RES	Investigative	[1]
Melanoma	DC6HNLZ	SK-MEL-2	Investigative	[1]
Non-small cell lung carcinoma	DCP8TWE	HOP-92	Investigative	[1]
Ovarian serous cystadenocarcinoma	DCQU80E	SK-OV-3	Investigative	[1]
Renal cell carcinoma	DCDOKSM	SN12C	Investigative	[1]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125976
• [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: 5893).
• [3] Isoniazid FDA Label
• [4] Novel agents in the management of Mycobacterium tuberculosis disease. Curr Med Chem. 2007;14(18):2000-8.
• [5] PLX4032 Mediated Melanoma Associated Antigen Potentiation in Patient Derived Primary Melanoma Cells. J Cancer. 2015 Oct 29;6(12):1320-30. doi: 10.7150/jca.11126. eCollection 2015.
• [6] Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation. EMBO J. 2016 Mar 1;35(5):462-78. doi: 10.15252/embj.201592081. Epub 2015 Dec 14.
• [7] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [8] Differential effects of the oncogenic BRAF inhibitor PLX4032 (vemurafenib) and its progenitor PLX4720 on ABCB1 function. J Pharm Pharm Sci. 2014;17(1):154-68.
• [9] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [10] Vemurafenib for the treatment of melanoma. Expert Opin Pharmacother. 2012 Dec;13(17):2533-43.
• [11] Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells. Elife. 2015 Aug 18;4:e04640. doi: 10.7554/eLife.04640.
• [12] Overcoming melanoma resistance to vemurafenib by targeting CCL2-induced miR-34a, miR-100 and miR-125b. Oncotarget. 2016 Jan 26;7(4):4428-41. doi: 10.18632/oncotarget.6599.
• [13] Melanoma Expressed-CD70 Is Regulated by RhoA and MAPK Pathways without Affecting Vemurafenib Treatment Activity. PLoS One. 2016 Feb 1;11(2):e0148095. doi: 10.1371/journal.pone.0148095. eCollection 2016.
• [14] Characterization of drug-specific signaling between primary human hepatocytes and immune cells. Toxicol Sci. 2017 Jul 1;158(1):76-89.
• [15] Diversity in enoyl-acyl carrier protein reductases. Cell Mol Life Sci. 2009 May;66(9):1507-17.
• [16] Inhibition of CYP2E1 catalytic activity in vitro by S-adenosyl-L-methionine. Biochem Pharmacol. 2005 Apr 1;69(7):1081-93.
• [17] Crystal structure of the catalase-peroxidase KatG W78F mutant from Synechococcus elongatus PCC7942 in complex with the antitubercular pro-drug isoniazid. FEBS Lett. 2015 Jan 2;589(1):131-7.
• [18] The actinobacterium Tsukamurella paurometabola has a functionally divergent arylamine N-acetyltransferase (NAT) homolog. World J Microbiol Biotechnol. 2019 Oct 31;35(11):174.
• [19] 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.
• [20] Determination of phospholipidosis potential based on gene expression analysis in HepG2 cells. Toxicol Sci. 2007 Mar;96(1):101-14.
• [21] Comparison of base-line and chemical-induced transcriptomic responses in HepaRG and RPTEC/TERT1 cells using TempO-Seq. Arch Toxicol. 2018 Aug;92(8):2517-2531.
• [22] Identification of differentially expressed genes in hepatic HepG2 cells treated with acetaminophen using suppression subtractive hybridization. Biol Pharm Bull. 2005 Jul;28(7):1148-53. doi: 10.1248/bpb.28.1148.
• [23] Auto-oxidation of Isoniazid Leads to Isonicotinic-Lysine Adducts on Human Serum Albumin. Chem Res Toxicol. 2015 Jan 20;28(1):51-8. doi: 10.1021/tx500285k. Epub 2014 Dec 9.
• [24] 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.
• [25] The Isoniazid Metabolites Hydrazine and Pyridoxal Isonicotinoyl Hydrazone Modulate Heme Biosynthesis. Toxicol Sci. 2019 Mar 1;168(1):209-224. doi: 10.1093/toxsci/kfy294.
• [26] Quercetin protected against isoniazide-induced HepG2 cell apoptosis by activating the SIRT1/ERK pathway. J Biochem Mol Toxicol. 2019 Sep;33(9):e22369. doi: 10.1002/jbt.22369. Epub 2019 Jul 23.
• [27] AMPK activator acadesine fails to alleviate isoniazid-caused mitochondrial instability in HepG2 cells. J Appl Toxicol. 2017 Oct;37(10):1219-1224. doi: 10.1002/jat.3483. Epub 2017 May 29.
• [28] Enhanced activation of human NK cells by drug-exposed hepatocytes. Arch Toxicol. 2020 Feb;94(2):439-448. doi: 10.1007/s00204-020-02668-8. Epub 2020 Feb 14.
• [29] Effects of N-acetyltransferase 2 (NAT2), CYP2E1 and Glutathione-S-transferase (GST) genotypes on the serum concentrations of isoniazid and metabolites in tuberculosis patients. J Toxicol Sci. 2008 May;33(2):187-95. doi: 10.2131/jts.33.187.
• [30] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1126165