Details of the Drug-Related molecule(s) Interaction Atlas

General Information of Drug (ID: DMJAEG6)

• Drug Name: VX-745 Drug Info
• Synonyms: 5-(2,6-Dichlorophenyl)-2-((2,4-difluorophenyl)thio)-6H-pyrimido[1,6-b]pyridazin-6-one; 209410-46-8; Neflamapimod; VX 745; VX745; VRT-031745; UNII-TYL52QM320; TYL52QM320; CHEBI:90528; 5-(2,6-dichlorophenyl)-2-(2,4-difluorophenylthio)-6H-pyrimido[1,6-b]pyridazin-6-one; 5-(2,6-dichlorophenyl)-2-(2,4-difluorophenyl)sulfanylpyrimido[1,6-b]pyridazin-6-one; Neflamapimod (USAN); Neflamapimod [USAN]; AK-44905; C19H9Cl2F2N3OS; 5-(2,6-Dichlorophenyl)-2-[(2,4-Difluorophenyl)sulfanyl]-6h-Pyrimido[1,6-B]pyridazin-6-One; VX745, VX-745; 5-(2,6-Dichlorophenyl)-2-((2,4-difluorophenyl)thio)-6H-pyrimido(1,6-b)pyridazin-6-one; Vertex 745 (VX745)

Indication

Disease Entry	ICD 11	Status	REF
Alzheimer disease	8A20	Phase 2	[1]
Rheumatoid arthritis	FA20	Phase 2	[2]

• Cross-matching ID:
  PubChem CID: 3038525
  ChEBI ID: CHEBI:90528
  CAS Number: CAS 209410-46-8
  TTD Drug ID: DMJAEG6

Molecule-Related Drug Atlas

Drug(s) Targeting Stress-activated protein kinase 2b (p38 beta)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
SB 235699	DMNH8XU	Psoriasis vulgaris	EA90	Discontinued in Phase 1	[4]
RO-316233	DMAGLPW	Discovery agent	N.A.	Investigative	[6]
Bisindolylmaleimide-I	DMOQJZC	Discovery agent	N.A.	Investigative	[6]
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole	DMN9YOB	Discovery agent	N.A.	Investigative	[7]
CI-1040	DMF3DZX	Discovery agent	N.A.	Investigative	[6]
KN-62	DMLZ89P	Discovery agent	N.A.	Investigative	[6]
Ro31-8220	DMDJLF0	Discovery agent	N.A.	Investigative	[6]
STAUROSPORINONE	DMU2H4K	Discovery agent	N.A.	Investigative	[6]
KT-5720	DM9J50F	Discovery agent	N.A.	Investigative	[6]
L-779450	DM51B74	Discovery agent	N.A.	Investigative	[8]

Drug(s) Targeting Stress-activated protein kinase 2a (p38 alpha)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Ozagrel	DMIGKA1	Xerophthalmia	5B55.Y	Phase 4	[9]
Losmapimod	DMIL37Z	Acute coronary syndrome	BA41	Phase 3	[9]
VX-702	DMKJDR6	Coronary artery disease	BA80	Phase 2a	[10]
Dilmapimod	DMBYJ92	Acute lung injury	NB32.3	Phase 2	[9]
PMID25991433-Compound-A1	DM89LF0	N. A.	N. A.	Patented	[11]
PMID25991433-Compound-F2	DM37VIQ	N. A.	N. A.	Patented	[11]
PMID25991433-Compound-L2	DM58UO9	N. A.	N. A.	Patented	[11]
PMID25991433-Compound-L3	DM3LWUR	N. A.	N. A.	Patented	[11]
PMID25991433-Compound-L1	DM2135Y	N. A.	N. A.	Patented	[11]
PMID25991433-Compound-O2	DMTROIQ	N. A.	N. A.	Patented	[11]

Drug(s) Targeting MAP kinase p38 (MAPK12)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
SM-101	DMFX9O6	Idiopathic thrombocytopenic purpura	3B64.10	Approved (orphan drug)	[12]
ARRY-797	DMJ48AB	Dilated cardiomyopathy	BC43.0	Phase 2	[13]
KC706	DMBX6C7	Cardiovascular disease	BA00-BE2Z	Discontinued in Phase 2	[14]
SB 235699	DMNH8XU	Psoriasis vulgaris	EA90	Discontinued in Phase 1	[15]
RO-316233	DMAGLPW	Discovery agent	N.A.	Investigative	[6]
Bisindolylmaleimide-I	DMOQJZC	Discovery agent	N.A.	Investigative	[6]
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole	DMN9YOB	Discovery agent	N.A.	Investigative	[7]
CI-1040	DMF3DZX	Discovery agent	N.A.	Investigative	[6]
AMP-PNP	DMTOK1D	Discovery agent	N.A.	Investigative	[16]
KN-62	DMLZ89P	Discovery agent	N.A.	Investigative	[6]

Drug(s) Affected By Interleukin-6 (IL6)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Methylprednisolone	DM4BDON	Acute adrenal insufficiency		Approved	[17]
Dexamethasone	DMMWZET	Acute adrenal insufficiency		Approved	[18]
Cannabidiol	DM0659E	Dravet syndrome	8A61.11	Approved	[19]
Pantothenic acid	DM091H2	Vitamin deficiency	5B55-5B71	Approved	[20]
Indinavir	DM0T3YH	Human immunodeficiency virus infection	1C62	Approved	[21]
Fulvestrant	DM0YZC6	Breast cancer	2C60-2C65	Approved	[22]
Hydrogen peroxide	DM1NG5W	Infectious disease	1A00-CA43.1	Approved	[23]
Imiquimod	DM1TMA3	Alopecia areata	ED70.2	Approved	[24]
Methimazole	DM25FL8	Hyperthyroidism	5A02	Approved	[25]
Methotrexate	DM2TEOL	Anterior urethra cancer		Approved	[17]

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
MAP kinase p38 (MAPK12)	TTYT93M	MK12_HUMAN	Inhibitor	[3]
Stress-activated protein kinase 2a (p38 alpha)	TTQBR95	MK14_HUMAN	Inhibitor	[4]
Stress-activated protein kinase 2b (p38 beta)	TT73U6C	MK11_HUMAN	Inhibitor	[4]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Protein Interaction/Cellular Processes	[5]
Vascular endothelial growth factor A, long form	OTIM9MZ3	VEGFA_HUMAN	Protein Interaction/Cellular Processes	[5]

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] 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: 5719).
• [3] P38 MAP kinase inhibitors as potential therapeutics for the treatment of joint degeneration and pain associated with osteoarthritis. J Inflamm (Lond). 2008 Dec 4;5:22.
• [4] Pharmacological inhibitors of MAPK pathways. Trends Pharmacol Sci. 2002 Jan;23(1):40-5.
• [5] Targeting p38 MAPK inhibits multiple myeloma cell growth in the bone marrow milieu. Blood. 2003 Jan 15;101(2):703-5. doi: 10.1182/blood-2002-06-1874. Epub 2002 Sep 5.
• [6] Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105.
• [7] Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. J Med Chem. 2004 Dec 2;47(25):6239-47.
• [8] The identification of potent and selective imidazole-based inhibitors of B-Raf kinase. Bioorg Med Chem Lett. 2006 Jan 15;16(2):378-81.
• [9] Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
• [10] Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: results of two randomized, double-blind, placebo-controlled clinical studies. Arthritis Rheum. 2009 May;60(5):1232-41.
• [11] c-Jun N-terminal kinase inhibitors: a patent review (2010 - 2014).Expert Opin Ther Pat. 2015;25(8):849-72.
• [12] Agents in development for the treatment of diabetic nephropathy. Expert Opin Emerg Drugs. 2008 Sep;13(3):447-63.
• [13] Array BioPharmas ARRY-797 Meets Primary Endpoint in Clinical Proof of Concept Trial in Osteoarthritis Patients Whose Pain is Poorly Controlled by NSAIDs
• [14] KC706, an Oral p38 MAP Kinase Inhibitor, Increases HDL-C. Circulation. 2007;116:II_126.
• [15] Synthesis and structure-activity relationship of aminobenzophenones. A novel class of p38 MAP kinase inhibitors with high antiinflammatory activity. J Med Chem. 2003 Dec 18;46(26):5651-62.
• [16] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [17] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [18] Mechanisms of dexamethasone-induced disturbed sleep and fatigue in paediatric patients receiving treatment for ALL. Eur J Cancer. 2010 Jul;46(10):1848-55. doi: 10.1016/j.ejca.2010.03.026. Epub 2010 Apr 17.
• [19] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [20] Calcium pantothenate modulates gene expression in proliferating human dermal fibroblasts. Exp Dermatol. 2009 Nov;18(11):969-78. doi: 10.1111/j.1600-0625.2009.00884.x. Epub 2009 Apr 8.
• [21] Some HIV antiretrovirals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages. Antivir Ther. 2007;12(4):489-500.
• [22] ERE-independent ERalpha target genes differentially expressed in human breast tumors. Mol Cell Endocrinol. 2005 Dec 21;245(1-2):53-9. doi: 10.1016/j.mce.2005.10.003. Epub 2005 Nov 17.
• [23] Oxidative Stress Alters miRNA and Gene Expression Profiles in Villous First Trimester Trophoblasts. Biomed Res Int. 2015;2015:257090. doi: 10.1155/2015/257090. Epub 2015 Aug 3.
• [24] (9)-Tetrahydrocannabinol Suppresses Monocyte-Mediated Astrocyte Production of Monocyte Chemoattractant Protein 1 and Interleukin-6 in a Toll-Like Receptor 7-Stimulated Human Coculture. J Pharmacol Exp Ther. 2019 Oct;371(1):191-201. doi: 10.1124/jpet.119.260661. Epub 2019 Aug 5.
• [25] Blood cell oxidative stress precedes hemolysis in whole blood-liver slice co-cultures of rat, dog, and human tissues. Toxicol Appl Pharmacol. 2010 May 1;244(3):354-65. doi: 10.1016/j.taap.2010.01.017. Epub 2010 Feb 6.