Details of the Drug Combination

General Information of Drug Combination (ID: DCTSVE6)

• Drug Combination Name: Meclofenamic acid + VR-776
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Meclofenamic acid (DM05FXR): Small molecular drug
  VR-776 (DMFQWNI): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 3.07
  Bliss Independence Score: 3.07
  Loewe Additivity Score: 17.7
  LHighest Single Agent (HSA) Score: 17.7

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Meclofenamic acid

Disease Entry	ICD 11	Status	REF
Ankylosing spondylitis	FA92.0	Approved	[2]
Dysmenorrhea	GA34.3	Approved	[3]
Joint pain	ME82	Approved	[2]
Menorrhagia	GA20.50	Approved	[3]
Osteoarthritis	FA00-FA05	Approved	[4]
Pain	MG30-MG3Z	Approved	[5]

Meclofenamic acid Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Prostaglandin G/H synthase (COX)	TTK0943	PGH1_HUMAN; PGH2_HUMAN	Inhibitor	[7]

Meclofenamic acid Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 102A1 (cyp102)	DE4OGUF	CPXB_BACMB	Metabolism	[8]

Meclofenamic acid Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Polyunsaturated fatty acid 5-lipoxygenase (ALOX5)	OT7FOIK2	LOX5_HUMAN	Decreases Activity	[9]
Sulfotransferase 1E1 (SULT1E1)	OTGPJ517	ST1E1_HUMAN	Decreases Activity	[10]
Sulfotransferase 1A1 (SULT1A1)	OT0K7JIE	ST1A1_HUMAN	Decreases Activity	[10]
Aldo-keto reductase family 1 member C3 (AKR1C3)	OTU2SXBA	AK1C3_HUMAN	Decreases Activity	[11]
Aldo-keto reductase family 1 member C2 (AKR1C2)	OTQ2XMO3	AK1C2_HUMAN	Decreases Activity	[11]
Aldo-keto reductase family 1 member C1 (AKR1C1)	OTQKR4CM	AK1C1_HUMAN	Decreases Activity	[11]
Aldo-keto reductase family 1 member C4 (AKR1C4)	OTW2MMOF	AK1C4_HUMAN	Decreases Activity	[12]
L-selectin (SELL)	OT6RAJZR	LYAM1_HUMAN	Decreases Expression	[13]

Indication(s) of VR-776

Disease Entry	ICD 11	Status	REF
Premature ejaculation	HA03.0Z	Discontinued in Phase 1	[6]

VR-776 Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[14]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[15]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[16]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[17]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[18]

References

• [1] 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.
• [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: 7219).
• [3] Use of meclofenamic acid in gynecology and obstetrics: effects on postsurgical stress. Clin J Pain. 1991;7 Suppl 1:S60-3.
• [4] Quantitation of indomethacin in serum and plasma using gas chromatography-mass spectrometry (GC-MS). Methods Mol Biol. 2010;603:297-305.
• [5] Meclofenamic Acid Restores Gefinitib Sensitivity by Downregulating Breast Cancer Resistance Protein and Multidrug Resistance Protein 7 via FTO/m6A-Demethylation/c-Myc in Non-Small Cell Lung Cancer. Front Oncol. 2022 Apr 21;12:870636.
• [6] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022099)
• [7] Interactions of PGH synthase isozymes-1 and -2 with NSAIDs. Ann N Y Acad Sci. 1994 Nov 15;744:50-7.
• [8] Both reactivity and accessibility are important in cytochrome P450 metabolism: a combined DFT and MD study of fenamic acids in BM3 mutants. J Chem Inf Model. 2019 Feb 25;59(2):743-753.
• [9] Meclofenamate sodium is an inhibitor of both the 5-lipoxygenase and cyclooxygenase pathways of the arachidonic acid cascade in vitro. Prostaglandins Leukot Med. 1986 Aug;23(2-3):229-38.
• [10] Inhibition of human phenol and estrogen sulfotransferase by certain non-steroidal anti-inflammatory agents. Curr Drug Metab. 2006 Oct;7(7):745-53.
• [11] Type 5 17beta-hydroxysteroid dehydrogenase/prostaglandin F synthase (AKR1C3): role in breast cancer and inhibition by non-steroidal anti-inflammatory drug analogs. Chem Biol Interact. 2009 Mar 16;178(1-3):221-7.
• [12] Initro CAPE inhibitory activity towards human AKR1C3 and the molecular basis. Chem Biol Interact. 2016 Jun 25;253:60-5.
• [13] Structure-function relationship and role of tumor necrosis factor-alpha-converting enzyme in the down-regulation of L-selectin by non-steroidal anti-inflammatory drugs. J Biol Chem. 2002 Oct 11;277(41):38212-21. doi: 10.1074/jbc.M205142200. Epub 2002 Jul 29.
• [14] Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol. 2007 Jul;151(6):737-48.
• [15] Erythromycin interaction with risperidone or clomipramine in an adolescent. J Child Adolesc Psychopharmacol. 1996 Summer;6(2):133-8.
• [16] Role of human UGT2B10 in N-glucuronidation of tricyclic antidepressants, amitriptyline, imipramine, clomipramine, and trimipramine. Drug Metab Dispos. 2010 May;38(5):863-70.
• [17] The biotransformation of clomipramine in vitro, identification of the cytochrome P450s responsible for the separate metabolic pathways. J Pharmacol Exp Ther. 1996 Jun;277(3):1659-64.
• [18] Serum clomipramine and desmethylclomipramine levels in a CYP2C19 and CYP2D6 intermediate metabolizer. Pharmacogenomics. 2017 May;18(7):601-605.