9SI2

Human DDR1 in complex with a pyrrolidine inhibitor

これはPDB形式変換不可エントリーです。

9SI2 の概要

• エントリーDOI: 10.2210/pdb9si2/pdb
• 分子名称: Epithelial discoidin domain-containing receptor 1, ~{N}-methyl-5-[(3~{S})-3-[2-methyl-5-[[3-(trifluoromethyl)phenyl]carbamoyl]phenyl]pyrrolidin-1-yl]pyridine-3-carboxamide, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: ddr1, tyrosine receptor kinase, transferase, discoidin domain, collagen
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35982.67

構造登録者

Rizzi, A.,Giuliani, M. (登録日: 2025-08-28, 公開日: 2026-07-29)

主引用文献

Carzaniga, L.,Rancati, F.,Rizzi, A.,Mazzucato, R.,Iotti, N.,Ghidini, E.,Bertolini, S.,Bignami, F.,Fioni, A.,Mileo, V.,Vaccaro, F.,Murgo, A.,Freire Bento, A.,Capelli, A.M.,Whittaker, B.P.,Levanto, S.,Chapman, R.S.L.,Hamasova, Z.,Hardy, C.J.,Clark, D.E.,Allen, R.,Briggs, M.A.,Hann, E.,Lee, S.,Matthews, C.,Todd, D.,Hawkins, J.,Giuliani, M.
A Journey through Scaffolds: Indolines, Pyrrolidines, and Azetidines in the Quest for Inhaled DDR Inhibitors for IPF.
J.Med.Chem., 69:6610-6633, 2026

PubMed Abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease, with excessive Extracellular Matrix (ECM) deposition impairing gas exchange, leading to lung failure. Current treatments are limited, with lung transplantation as the only cure. Discoidin Domain Receptors (DDR1/2), collagen-activated receptor tyrosine kinases, orchestrate collagen deposition in fibrotic diseases. We report the discovery and optimization of novel DDR1/2 kinase-domain inhibitors suitable for inhaled administration. Starting from a benzylamine scaffold, three chemical series, namely indolines, pyrrolidines, and azetidines, were explored. The first two showed potent DDR1 inhibition and lung retention but faced safety and selectivity challenges. The azetidine compound was identified as the most promising one for its nanomolar potency, improved kinase selectivity, reduced cardiotoxicity risk, and excellent inhaled PK profile. It demonstrated activity in a collagen-induced pharmacodynamic mouse model, supporting its potential as an inhaled DDR inhibitor for IPF and validating the azetidine scaffold as a promising starting point for further optimization.

PubMed: 41715301
DOI: 10.1021/acs.jmedchem.5c02830

実験手法

X-RAY DIFFRACTION (2.12 Å)