Details of the Drug Combination

General Information of Drug Combination (ID: DCSHU7U)

Drug Combination Name

Diazoxide SCH 727965

Indication

Disease Entry	Status	REF
Chronic myelogenous leukemia	Investigative	[1]

Component Drugs

Diazoxide DML1538

SCH 727965 DMCJLD1

Small molecular drug

2D MOL

3D MOL

High-throughput Screening Result

Testing Cell Line: KBM-7

Zero Interaction Potency (ZIP) Score: 0.31

Bliss Independence Score: 0.31

Loewe Additivity Score: 0.95

LHighest Single Agent (HSA) Score: 0.95

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)

Indication(s) of Diazoxide

Disease Entry	ICD 11	Status	REF
Congenital hyperinsulinism	5A4Y	Approved	[2]
Hyperinsulinemia	5A4Y	Approved	[2]
Hypertension	BA00-BA04	Approved	[3]
Hypertensive emergency	BA03	Approved	[2]
Insulinoma	2C10.1	Approved	[2]
Malignant essential hypertension	BA00	Approved	[2]

Diazoxide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Potassium channel unspecific (KC)	TT1VOHK	NOUNIPROTAC	Modulator	[5]
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Diazoxide Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Secretion	[6]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Secretion	[6]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Increases Activity	[7]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Decreases Secretion	[6]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[8]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Decreases Expression	[8]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Increases Expression	[7]
ATP-sensitive inward rectifier potassium channel 11 (KCNJ11)	OTPUUELV	KCJ11_HUMAN	Decreases Expression	[9]
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⏷ Show the Full List of 8 DOT(s)

Indication(s) of SCH 727965

Disease Entry	ICD 11	Status	REF
Acute lymphoblastic leukaemia	2A85	Discontinued in Phase 3	[4]

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	[10]
Cyclin-dependent kinase 1 (CDK1)	TTH6V3D	CDK1_HUMAN	Inhibitor	[10]
Cyclin-dependent kinase 2 (CDK2)	TT7HF4W	CDK2_HUMAN	Inhibitor	[10]
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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	[11]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[11]
Breast cancer type 1 susceptibility protein (BRCA1)	OT5BN6VH	BRCA1_HUMAN	Decreases Expression	[12]
Breast cancer type 2 susceptibility protein (BRCA2)	OTF1XSV1	BRCA2_HUMAN	Decreases Expression	[12]
DNA repair protein RAD51 homolog 1 (RAD51)	OTNVWGC1	RAD51_HUMAN	Decreases Expression	[12]
Fanconi anemia group D2 protein (FANCD2)	OTVEB5LF	FACD2_HUMAN	Decreases Expression	[12]
Cyclin-dependent kinase 12 (CDK12)	OTZUDGNU	CDK12_HUMAN	Decreases Activity	[12]
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⏷ Show the Full List of 7 DOT(s)

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	Diazoxide FDA Label
3	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: 2409).
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: 7379).
5	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
6	Antihypertensive drugs clonidine, diazoxide, hydralazine and furosemide regulate the production of cytokines by placentas and peripheral blood mononuclear cells in normal pregnancy. J Hypertens. 2006 May;24(5):915-22. doi: 10.1097/01.hjh.0000222762.84605.03.
7	Diazoxide-mediated preconditioning against apoptosis involves activation of cAMP-response element-binding protein (CREB) and NFkappaB. J Biol Chem. 2004 Nov 5;279(45):46748-54. doi: 10.1074/jbc.M406217200. Epub 2004 Aug 23.
8	Diazoxide-mediated growth inhibition in human lung cancer cells via downregulation of beta-catenin-mediated cyclin D1 transcription. Lung. 2009 Jan-Feb;187(1):61-7. doi: 10.1007/s00408-008-9127-1. Epub 2008 Dec 4.
9	Combined contributions of over-secreted glucagon-like peptide 1 and suppressed insulin secretion to hyperglycemia induced by gatifloxacin in rats. Toxicol Appl Pharmacol. 2013 Feb 1;266(3):375-84. doi: 10.1016/j.taap.2012.11.015. Epub 2012 Nov 28.
10	Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
11	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.
12	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.