6ZE8

Crystal structure of human chitotriosidase-1 (hCHIT) catalytic domain in complex with compound OATD-01

6ZE8 の概要

• エントリーDOI: 10.2210/pdb6ze8/pdb
• 分子名称: Chitotriosidase-1, 5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-4H-1,2,4-triazol-3-amine, SODIUM ION, ... (5 entities in total)
• 機能のキーワード: chitinase, chitin binding, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 247283.66

構造登録者

Nowotny, M.,Bartlomiejczak, A.,Napiorkowska-Gromadzka, A. (登録日: 2020-06-16, 公開日: 2020-11-11, 最終更新日: 2024-10-23)

主引用文献

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.
Discovery of OATD-01 , a First-in-Class Chitinase Inhibitor as Potential New Therapeutics for Idiopathic Pulmonary Fibrosis.
J.Med.Chem., 63:15527-15540, 2020

PubMed Abstract: Chitotriosidase (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 led to the identification of compound (, a highly active CHIT1 inhibitor with both an excellent PK profile in multiple species and selectivity against a panel of other off-targets. 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. is the first-in-class CHIT1 inhibitor, currently completed phase 1b of clinical trials, to be a potential treatment for IPF.

PubMed: 33078933
DOI: 10.1021/acs.jmedchem.0c01179

実験手法

X-RAY DIFFRACTION (1.5 Å)