Details of the Drug Combination

General Information of Drug Combination (ID: DC80V1O)

• Drug Combination Name: Metformin + MK-1775
• Indication: Adenocarcinoma; Status: Investigative [1]
• Component Drugs:
  Metformin (DM89QE1): Small molecular drug
  MK-1775 (DM3WDZ5): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: HT29
  Zero Interaction Potency (ZIP) Score: 8.74
  Bliss Independence Score: 11.44
  Loewe Additivity Score: 7.56
  LHighest Single Agent (HSA) Score: 10.34

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Metformin

Disease Entry	ICD 11	Status	REF
Colorectal carcinoma	N.A.	Approved	[2]
Non-insulin dependent diabetes	5A11	Approved	[2]
Ovarian serous cystadenocarcinoma	N.A.	Approved	[2]
Prostate carcinoma	N.A.	Approved	[2]
Type-2 diabetes	5A11	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Investigative	[4]

Metformin Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Acetyl-CoA carboxylase 2 (ACACB)	TTY84UG	ACACB_HUMAN	Activator	[7]
Solute carrier family 47 member 1 (SLC47A1)	TTMHCGA	S47A1_HUMAN	Modulator	[8]
HUMAN mannose receptor (MRC1)	TTKV8W5	MRC1_HUMAN	Inhibitor	[4]

Metformin Interacts with 9 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[9]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[10]
Multidrug and toxin extrusion protein 1 (SLC47A1)	DTZGT0P	S47A1_HUMAN	Substrate	[11]
Organic cation transporter 3 (SLC22A3)	DT6201N	S22A3_HUMAN	Substrate	[12]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[10]
Multidrug and toxin extrusion protein 2 (SLC47A2)	DT3TX4H	S47A2_HUMAN	Substrate	[13]
Thiamine transporter 1 (SLC19A2)	DTLA4Q2	S19A2_HUMAN	Substrate	[14]
Thiamine transporter 2 (SLC19A3)	DT39CEA	S19A3_HUMAN	Substrate	[14]
Equilibrative nucleoside transporter 4 (SLC29A4)	DT3EAQP	S29A4_HUMAN	Substrate	[15]

Indication(s) of MK-1775

Disease Entry	ICD 11	Status	REF
Ovarian cancer	2C73	Phase 2	[5]
Solid tumour/cancer	2A00-2F9Z	Phase 1	[6]

MK-1775 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Wee1-like protein kinase (WEE1)	TTJFOAL	WEE1_HUMAN	Inhibitor	[17]

MK-1775 Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Decreases Phosphorylation	[16]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Response To Substance	[16]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adenocarcinoma	DCHG1K0	OVCAR3	Investigative	[1]
Adenocarcinoma	DC5KMKA	NCIH1650	Investigative	[1]
Adenocarcinoma	DC82WND	NCIH2122	Investigative	[1]
Adenocarcinoma	DCP2M11	NCIH520	Investigative	[1]
Ewing sarcoma-peripheral primitive neuroectodermal tumour	DCKMZT6	ES2	Investigative	[1]
Large cell lung carcinoma	DCQUVN3	NCI-H460	Investigative	[1]
Breast carcinoma	DCL3ITK	OCUBM	Investigative	[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] Metformin FDA Label
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing. March 2020
• [5] 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: 7702).
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] AMP-activated protein kinase-dependent and -independent mechanisms underlying in vitro antiglioma action of compound C. Biochem Pharmacol. 2009 Jun 1;77(11):1684-93.
• [8] Molecular cloning, functional characterization and tissue distribution of rat H+/organic cation antiporter MATE1. Pharm Res. 2006 Aug;23(8):1696-701.
• [9] Role of human placental apical membrane transporters in the efflux of glyburide, rosiglitazone, and metformin. Am J Obstet Gynecol. 2010 Apr;202(4):383.e1-7.
• [10] Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. Drug Metab Pharmacokinet. 2005 Oct;20(5):379-86.
• [11] Human multidrug and toxin extrusion 1 (MATE1/SLC47A1) transporter: functional characterization, interaction with OCT2 (SLC22A2), and single nucleotide polymorphisms. Am J Physiol Renal Physiol. 2010 Apr;298(4):F997-F1005.
• [12] Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver. Hepatology. 2009 Oct;50(4):1227-40.
• [13] Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. Biochem Pharmacol. 2007 Jul 15;74(2):359-71.
• [14] Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3). Mol Pharm. 2015 Dec 7;12(12):4301-10.
• [15] Metformin: from mechanisms of action to therapies. Cell Metab. 2014 Dec 2;20(6):953-66.
• [16] Functional kinomics identifies candidate therapeutic targets in head and neck cancer. Clin Cancer Res. 2014 Aug 15;20(16):4274-88. doi: 10.1158/1078-0432.CCR-13-2858.
• [17] A novel c-Met inhibitor, MK8033, synergizes with carboplatin plus paclitaxel to inhibit ovarian cancer cell growth. Oncol Rep. 2013 May;29(5):2011-8.
• [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.