Details of the Drug Combination

General Information of Drug Combination (ID: DC97D1X)

• Drug Combination Name: Metformin + SCH 727965
• Indication: Breast and ovarian cancer syndrome; Status: Investigative [1]
• Component Drugs:
  Metformin (DM89QE1): Small molecular drug
  SCH 727965 (DMCJLD1): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: UWB1289+BRCA1
  Zero Interaction Potency (ZIP) Score: 2.19
  Bliss Independence Score: 2.44
  Loewe Additivity Score: 2.08
  LHighest Single Agent (HSA) Score: 3.26

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	[6]
Solute carrier family 47 member 1 (SLC47A1)	TTMHCGA	S47A1_HUMAN	Modulator	[7]
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	[8]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[9]
Multidrug and toxin extrusion protein 1 (SLC47A1)	DTZGT0P	S47A1_HUMAN	Substrate	[10]
Organic cation transporter 3 (SLC22A3)	DT6201N	S22A3_HUMAN	Substrate	[11]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[9]
Multidrug and toxin extrusion protein 2 (SLC47A2)	DT3TX4H	S47A2_HUMAN	Substrate	[12]
Thiamine transporter 1 (SLC19A2)	DTLA4Q2	S19A2_HUMAN	Substrate	[13]
Thiamine transporter 2 (SLC19A3)	DT39CEA	S19A3_HUMAN	Substrate	[13]
Equilibrative nucleoside transporter 4 (SLC29A4)	DT3EAQP	S29A4_HUMAN	Substrate	[14]

Indication(s) of SCH 727965

Disease Entry	ICD 11	Status	REF
Acute lymphoblastic leukaemia	2A85	Discontinued in Phase 3	[5]

SCH 727965 Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Cyclin-dependent kinase 9 (CDK9)	TT1LVF2	CDK9_HUMAN	Inhibitor	[15]
Cyclin-dependent kinase 1 (CDK1)	TTH6V3D	CDK1_HUMAN	Inhibitor	[15]
Cyclin-dependent kinase 2 (CDK2)	TT7HF4W	CDK2_HUMAN	Inhibitor	[15]

SCH 727965 Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Phosphorylation	[16]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[16]
Breast cancer type 1 susceptibility protein (BRCA1)	OT5BN6VH	BRCA1_HUMAN	Decreases Expression	[17]
Breast cancer type 2 susceptibility protein (BRCA2)	OTF1XSV1	BRCA2_HUMAN	Decreases Expression	[17]
DNA repair protein RAD51 homolog 1 (RAD51)	OTNVWGC1	RAD51_HUMAN	Decreases Expression	[17]
Fanconi anemia group D2 protein (FANCD2)	OTVEB5LF	FACD2_HUMAN	Decreases Expression	[17]
Cyclin-dependent kinase 12 (CDK12)	OTZUDGNU	CDK12_HUMAN	Decreases Activity	[17]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adenocarcinoma	DCXI6UM	NCIH2122	Investigative	[18]
Adenocarcinoma	DCWMK6B	NCIH520	Investigative	[18]
Adenocarcinoma	DCAJO7N	HT29	Investigative	[18]
Ewing sarcoma-peripheral primitive neuroectodermal tumour	DCJNORO	ES2	Investigative	[18]
Malignant melanoma	DCAPSCC	RPMI7951	Investigative	[18]
Breast carcinoma	DCZC4LL	OCUBM	Investigative	[1]
Carcinoma	DCKCT4P	OV90	Investigative	[1]
Invasive ductal carcinoma	DCDLBW8	T-47D	Investigative	[1]

References

• [1] 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.
• [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: 7379).
• [6] 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.
• [7] Molecular cloning, functional characterization and tissue distribution of rat H+/organic cation antiporter MATE1. Pharm Res. 2006 Aug;23(8):1696-701.
• [8] 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.
• [9] Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. Drug Metab Pharmacokinet. 2005 Oct;20(5):379-86.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3). Mol Pharm. 2015 Dec 7;12(12):4301-10.
• [14] Metformin: from mechanisms of action to therapies. Cell Metab. 2014 Dec 2;20(6):953-66.
• [15] Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
• [16] Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol Cancer Ther. 2010 Aug;9(8):2344-53. doi: 10.1158/1535-7163.MCT-10-0324. Epub 2010 Jul 27.
• [17] CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer. Cell Rep. 2016 Nov 22;17(9):2367-2381. doi: 10.1016/j.celrep.2016.10.077.
• [18] 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.