Details of the Drug Combination

General Information of Drug Combination (ID: DCRGD4U)

• Drug Combination Name: Diazoxide + Mesalazine
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Diazoxide (DML1538): Small molecular drug
  Mesalazine (DMOL5IU): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 2.86
  Bliss Independence Score: 2.86
  Loewe Additivity Score: 3.29
  LHighest Single Agent (HSA) Score: 3.29

Molecular Interaction Atlas of This Drug Combination

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	[8]

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	[9]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Secretion	[9]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Increases Activity	[10]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Decreases Secretion	[9]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[11]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Decreases Expression	[11]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Increases Expression	[10]
ATP-sensitive inward rectifier potassium channel 11 (KCNJ11)	OTPUUELV	KCJ11_HUMAN	Decreases Expression	[12]

Indication(s) of Mesalazine

Disease Entry	ICD 11	Status	REF
Diverticulitis	N.A.	Approved	[4]
Proctitis	DB33.Z	Approved	[5]
Ulcerative colitis	DD71	Approved	[6]
Ulcerative proctosigmoiditis	N.A.	Approved	[7]

Mesalazine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Prostaglandin G/H synthase 1 (COX-1)	TT8NGED	PGH1_HUMAN	Inhibitor	[13]

Mesalazine Interacts with 4 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[14]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[15]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[15]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[15]

Mesalazine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
RNA cytidine acetyltransferase (hALP)	DEZV4AP	NAT10_HUMAN	Metabolism	[16]

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] Colonic diverticular disease. Nat Rev Dis Primers. 2020 Mar 26;6(1):20.
• [5] Optimized Management of Ulcerative Proctitis: When and How to Use Mesalazine Suppository. Digestion. 2018;97(1):59-63.
• [6] 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: 4655).
• [7] Efficacy of Oral, Topical, or Combined Oral and Topical 5-Aminosalicylates, in Ulcerative Colitis: Systematic Review and Network Meta-analysis. J Crohns Colitis. 2021 Jul 5;15(7):1184-1196.
• [8] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [14] Transport studies with 5-aminosalicylate. Eur J Clin Pharmacol. 2006 Oct;62(10):871-5.
• [15] Role of organic anion-transporting polypeptides for cellular mesalazine (5-aminosalicylic acid) uptake. Drug Metab Dispos. 2011 Jun;39(6):1097-102.
• [16] NAT1 genotypes do not predict response to mesalamine in patients with ulcerative colitis. Z Gastroenterol. 2008 Mar;46(3):259-65.