Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT8VUE0)

• DTT Name: Chymase (CYM)
• Synonyms: Mast cell protease I; CYH; Alpha-chymase
• Gene Name: CMA1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Peptidase
• UniProt ID: CMA1_HUMAN
• TTD ID: T05114
• EC Number: EC 3.4.21.39
• Sequence:
  MLLLPLPLLLFLLCSRAEAGEIIGGTECKPHSRPYMAYLEIVTSNGPSKFCGGFLIRRNF
  VLTAAHCAGRSITVTLGAHNITEEEDTWQKLEVIKQFRHPKYNTSTLHHDIMLLKLKEKA
  SLTLAVGTLPFPSQFNFVPPGRMCRVAGWGRTGVLKPGSDTLQEVKLRLMDPQACSHFRD
  FDHNLQLCVGNPRKTKSAFKGDSGGPLLCAGVAQGIVSYGRSDAKPPAVFTRISHYRPWI
  NQILQAN
• Function: Major secreted protease of mast cells with suspected roles in vasoactive peptide generation, extracellular matrix degradation, and regulation of gland secretion.
• KEGG Pathway: Renin-angiotensin system (hsa04614)
• Reactome Pathway:
  Metabolism of Angiotensinogen to Angiotensins (R-HSA-2022377)
  Activation of Matrix Metalloproteinases (R-HSA-1592389)

Molecular Interaction Atlas (MIA) of This DTT

5 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ASB17061	DMNVU28	Atopic dermatitis	EA80	Phase 2	[2]
BAY 11-42524	DM8SNEM	Left ventricular dysfunction	BD11	Phase 2	[1]
BAY 1142524	DMHKTGX	Myocardial infarction	BA41-BA43	Phase 2	[3]
JNJ-10311795	DM7OTQS	Chronic obstructive pulmonary disease	CA22	Phase 2	[4]
SUN13834	DMPK34E	Gram-positive bacterial infection	1B74-1G40	Phase 2	[5]

10 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-(N-Morpholino)-Ethanesulfonic Acid	DMZVHSB	Discovery agent	N.A.	Investigative	[6]
BCEAB	DM047DQ	Discovery agent	N.A.	Investigative	[7]
Benzylsulfinic Acid	DM7XK28	Discovery agent	N.A.	Investigative	[8]
CHYMOSTATIN	DMT27QD	Discovery agent	N.A.	Investigative	[9]
KM-01221	DMG594K	Cardiovascular disease	BA00-BE2Z	Investigative	[10]
NK3201	DM9WC1T	Discovery agent	N.A.	Investigative	[11]
Phenylalanylmethane	DMZNFT2	Discovery agent	N.A.	Investigative	[6]
Rac-2q	DMD5TPH	Discovery agent	N.A.	Investigative	[9]
SUN-C8257	DM26KQG	Discovery agent	N.A.	Investigative	[12]
Y-40613	DM412IV	Discovery agent	N.A.	Investigative	[13]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Atopic dermatitis	EA90	Skin	1.20E-03	-0.92	-1.08
Chronic obstructive pulmonary disease	CA23	Lung tissue	3.49E-01	-0.09	-0.12
Chronic obstructive pulmonary disease	CA23	Small airway epithelium	2.27E-01	0.07	0.4
Asthma	CA23	Nasal and bronchial airway	2.97E-02	-0.08	-0.17
Multiple myeloma	2C82	Bone marrow	3.36E-05	-0.62	-3.21

References

• [1] ClinicalTrials.gov (NCT02452515) A Single-blind Pilot Study to Investigate Safety and Tolerability of the Chymase Inhibitor BAY1142524 in Clinically Stable Patients With Left-ventricular Dysfunction.
• [2] Immunology of atopic eczema: overcoming the Th1/Th2 paradigm. Allergy. 2013 Aug;68(8):974-82.
• [3] Pharmacokinetics, Safety, and Tolerability of the Novel Chymase Inhibitor BAY 1142524 in Healthy Male Volunteers. Clin Pharmacol Drug Dev. 2019 May;8(4):467-479.
• [4] Discovery of potent, selective, orally active, nonpeptide inhibitors of human mast cell chymase. J Med Chem. 2007 Apr 19;50(8):1727-30.
• [5] Oral chymase inhibitor SUN13834 ameliorates skin inflammation as well as pruritus in mouse model for atopic dermatitis.Eur J Pharmacol.2008 Dec 28;601(1-3):186-91.
• [6] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [7] Development of a chymase inhibitor: pharmacological characterization of a chymase inhibitor in inflamed tissue remodeling and fibrosis. Jpn J Pharmacol. 2002 Nov;90(3):206-9.
• [8] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [9] Identification of 6-substituted 4-arylsulfonyl-1,4-diazepane-2,5-diones as a novel scaffold for human chymase inhibitors. Bioorg Med Chem Lett. 2007 Jun 15;17(12):3431-4.
• [10] 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. (Target id: 2340).
• [11] Impact of chymase inhibitor on cardiac function and survival after myocardial infarction. Cardiovasc Res. 2003 Nov 1;60(2):413-20.
• [12] Chymase inhibitor ameliorates eosinophilia in mice infected with Nippostrongylus brasiliensis. Int Arch Allergy Immunol. 2002 Jul;128(3):235-9.
• [13] Therapeutic potential of a specific chymase inhibitor in atopic dermatitis. Jpn J Pharmacol. 2002 Nov;90(3):214-7.