6ze8
Crystal structure of human chitotriosidase-1 (hCHIT) catalytic domain in complex with compound OATD-01Crystal structure of human chitotriosidase-1 (hCHIT) catalytic domain in complex with compound OATD-01
Structural highlights
Publication Abstract from PubMedChitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase) are the enzymatically active chitinases that have been implicated in the pathology of chronic lung diseases such as asthma and interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis. The clinical and preclinical data suggest that pharmacological inhibition of CHIT1 might represent a novel therapeutic approach in IPF. Structural modification of an advanced lead molecule 3 led to the identification of compound 9 (OATD-01), a highly active CHIT1 inhibitor with both an excellent PK profile in multiple species and selectivity against a panel of other off-targets. OATD-01 given orally once daily in a range of doses between 30 and 100 mg/kg showed significant antifibrotic efficacy in an animal model of bleomycin-induced pulmonary fibrosis. OATD-01 is the first-in-class CHIT1 inhibitor, currently completed phase 1b of clinical trials, to be a potential treatment for IPF. Discovery of OATD-01, a First-in-Class Chitinase Inhibitor as Potential New Therapeutics for Idiopathic Pulmonary Fibrosis.,Koralewski R, Dymek B, Mazur M, Sklepkiewicz P, Olejniczak S, Czestkowski W, Matyszewski K, Andryianau G, Niedziejko P, Kowalski M, Gruza M, Borek B, Jedrzejczak K, Bartoszewicz A, Pluta E, Rymaszewska A, Kania M, Rejczak T, Piasecka S, Mlacki M, Mazurkiewicz M, Piotrowicz M, Salamon M, Zagozdzon A, Napiorkowska-Gromadzka A, Bartlomiejczak A, Mozga W, Dobrzanski P, Dzwonek K, Golab J, Nowotny M, Olczak J, Golebiowski A J Med Chem. 2020 Oct 20. doi: 10.1021/acs.jmedchem.0c01179. PMID:33078933[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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