Details of the Drug Combination

General Information of Drug Combination (ID: DCTPD8J)

• Drug Combination Name: Nitrosoglutathione + Sivelestat
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Nitrosoglutathione (DMZ9WI4): N.A.
  Sivelestat (DM6BZCV): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 11.89
  Bliss Independence Score: 11.89
  Loewe Additivity Score: 24.35
  LHighest Single Agent (HSA) Score: 24.35

Molecular Interaction Atlas of This Drug Combination

Nitrosoglutathione Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
S-(hydroxymethyl)glutathione dehydrogenase (adh)	DEAH3PE	A0A0A7DS01_VIBCL	Metabolism	[5]

Nitrosoglutathione Interacts with 19 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Serine protease HTRA2, mitochondrial (HTRA2)	OTC7616F	HTRA2_HUMAN	Affects Localization	[6]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases Secretion	[7]
Interferon gamma (IFNG)	OTXG9JM7	IFNG_HUMAN	Increases Secretion	[7]
C-X-C motif chemokine 10 (CXCL10)	OTTLQ6S0	CXL10_HUMAN	Decreases Secretion	[7]
Interleukin-5 (IL5)	OTAFPSCO	IL5_HUMAN	Decreases Secretion	[7]
Transcription factor Sp1 (SP1)	OTISPT4X	SP1_HUMAN	Increases Activity	[8]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[9]
C-C motif chemokine 5 (CCL5)	OTSCA5CK	CCL5_HUMAN	Decreases Secretion	[7]
Cystic fibrosis transmembrane conductance regulator (CFTR)	OT6B22QH	CFTR_HUMAN	Decreases Expression	[8]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Decreases Secretion	[7]
Interleukin-12 subunit beta (IL12B)	OT0JF8A3	IL12B_HUMAN	Decreases Expression	[7]
T-lymphocyte activation antigen CD86 (CD86)	OTJCSBPC	CD86_HUMAN	Decreases Expression	[7]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[6]
Transcription factor Sp3 (SP3)	OTYDQZ1T	SP3_HUMAN	Decreases Activity	[8]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[6]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Increases Expression	[10]
Carbonyl reductase 1 (CBR1)	OTQ3A541	CBR1_HUMAN	Increases Reduction	[11]
Serine-protein kinase ATM (ATM)	OTQVOHLT	ATM_HUMAN	Increases Response To Substance	[12]
Alcohol dehydrogenase class-3 (ADH5)	OTSO67MI	ADHX_HUMAN	Increases Reduction	[13]

Indication(s) of Sivelestat

Disease Entry	ICD 11	Status	REF
Crohn disease	DD70	Phase 3	[2]
Multiple sclerosis	8A40	Phase 3	[2]
Psoriatic arthritis	FA21	Phase 3	[2]
Pyoderma gangrenosum	EB21	Phase 3	[3]
Rheumatoid arthritis	FA20	Phase 3	[2]
Ulcerative colitis	DD71	Phase 3	[2]
Anterior uveitis	9A96	Application submitted	[4]
Axial spondyloarthritis	FA92.0	Application submitted	[2]

Sivelestat Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Pancreatic elastase 1 (CELA1)	TT3NKIB	CELA1_HUMAN	Inhibitor	[14]
Neutrophil elastase (NE)	TTPLTSQ	ELNE_HUMAN	Inhibitor	[15]

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] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] Nitrosative stress response in Vibrio cholerae: role of S-nitrosoglutathione reductase. Appl Biochem Biotechnol. 2017 Jul;182(3):871-884.
• [6] The induction of reactive oxygen species and loss of mitochondrial Omi/HtrA2 is associated with S-nitrosoglutathione-induced apoptosis in human endothelial cells. Toxicol Appl Pharmacol. 2010 May 1;244(3):374-84. doi: 10.1016/j.taap.2010.02.004. Epub 2010 Feb 11.
• [7] Regulatory role of nitric oxide on monocyte-derived dendritic cell functions. J Interferon Cytokine Res. 2003 Aug;23(8):423-31. doi: 10.1089/107999003322277838.
• [8] Concentration-dependent effects of endogenous S-nitrosoglutathione on gene regulation by specificity proteins Sp3 and Sp1. Biochem J. 2004 May 15;380(Pt 1):67-74. doi: 10.1042/BJ20031687.
• [9] Induction of heme oxygenase-1 as a response in sensing the signals evoked by distinct nitric oxide donors. Biochem Pharmacol. 1999 Jul 15;58(2):227-36. doi: 10.1016/s0006-2952(99)00097-0.
• [10] Regulation of the hypoxia-inducible factor 1alpha by the inflammatory mediators nitric oxide and tumor necrosis factor-alpha in contrast to desferroxamine and phenylarsine oxide. J Biol Chem. 2001 Oct 26;276(43):39805-11. doi: 10.1074/jbc.M107689200. Epub 2001 Aug 20.
• [11] Studies on reduction of S-nitrosoglutathione by human carbonyl reductases 1 and 3. Chem Biol Interact. 2011 May 30;191(1-3):95-103.
• [12] Hypersensitivity of ataxia-telangiectasia fibroblasts to a nitric oxide donor. Free Radic Biol Med. 1997;22(1-2):343-7. doi: 10.1016/s0891-5849(96)00336-x.
• [13] The Janus face of alcohol dehydrogenase 3. Chem Biol Interact. 2009 Mar 16;178(1-3):29-35. doi: 10.1016/j.cbi.2008.10.050. Epub 2008 Nov 6.
• [14] Sivelestat (selective neutrophil elastase inhibitor) improves the mortality rate of sepsis associated with both acute respiratory distress syndrome... Shock. 2010 Jan;33(1):14-8.
• [15] Neutrophil elastase inhibitor (sivelestat) reduces the levels of inflammatory mediators by inhibiting NF-kB. Inflamm Res. 2009 Apr;58(4):198-203.