9JA8

Crystal structure of human phosphodiesterase 10A in complex with N-(2-amino-2-thioxoethyl)-2-(3-(3-(dimethylcarbamoyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)azetidin-1-yl)quinoline-4-carboxamide

これはPDB形式変換不可エントリーです。

9JA8 の概要

• エントリーDOI: 10.2210/pdb9ja8/pdb
• 分子名称: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ~{N}-(2-azanyl-2-sulfanylidene-ethyl)-2-[3-[3-(dimethylcarbamoyl)-6-fluoranyl-imidazo[1,2-a]pyridin-2-yl]azetidin-1-yl]quinoline-4-carboxamide, ZINC ION, ... (5 entities in total)
• 機能のキーワード: inhibitor, complex, pde10a, idiopathic pulmonary fibrosis, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 75770.42

構造登録者

Zhang, F.C.,Huang, Y.Y.,Luo, H.B.,Guo, L. (登録日: 2024-08-24, 公開日: 2025-01-29)

主引用文献

Wang, Q.,Liu, X.,Yuan, H.,Zhang, F.,Wu, J.,Yang, D.,Qian, J.,Huang, Y.Y.,Chai, G.,Luo, H.B.,Guo, L.
Inhalable Carbonyl Sulfide Donor-Hybridized Selective Phosphodiesterase 10A Inhibitor for Treating Idiopathic Pulmonary Fibrosis by Inhibiting Tumor Growth Factor-beta Signaling and Activating the cAMP/Protein Kinase A/cAMP Response Element-Binding Protein (CREB)/p53 Axis.
Acs Pharmacol Transl Sci, 8:256-269, 2025

PubMed Abstract: Idiopathic pulmonary fibrosis (IPF) is a debilitating, incurable, and life-threatening disease that lacks effective therapy. The overexpression of phosphodiesterase 10A (PDE10A) plays a vital role in pulmonary fibrosis (PF). However, the impact of selective PDE10A inhibitors on the tumor growth factor-β (TGF-β)/small mother against decapentaplegic (Smad) signaling pathway remains unclear. Herein, we have exploited a novel carbonyl sulfide (COS)/hydrogen sulfide (HS)-donor hybrid PDE10A inhibitor called with a well-defined mechanism of HS-releasing action. It exhibited highly potent inhibitory activity against PDE10A and excellent PDE subfamily selectivity. Moreover, demonstrated significant antifibrotic effects by inhibiting cell proliferation and mitigating fibroblast-to-myofibroblast transition (FMT). A dry powder inhalation formulation called has been developed using the ultrasonic spray freeze drying (USFD) technique, demonstrating significant antifibrotic efficacy in mice with bleomycin-induced PF at a dosage approximately 600 times lower than pirfenidone. This remarkable antifibrotic efficacy of on TGF-β1-induced FMT could be primarily attributed to its inhibition of the Smad2/Smad3 phosphorylation. Moreover, effectively attenuated fibrosis in MRC-5 cells by activating the cAMP/protein kinase A (PKA)/CREB pathway and potentially increasing levels of p53 protein. Our findings suggest that effective inhibition of PDE10A potentially confers a protective effect on FMT in PF by impeding TGF-β signaling and activating the cAMP/PKA/CREB/p53 axis.

PubMed: 39816787
DOI: 10.1021/acsptsci.4c00671

実験手法

X-RAY DIFFRACTION (2.4 Å)