Discovery of Pyrazolo[3,4- <i>d</i> ]pyridazinone Derivatives as Selective DDR1 Inhibitors via Deep Learning Based Design, Synthesis, and Biological Evaluation
Xiaoqin Tan, Chunpu Li, Ruirui Yang, Sen Zhao, Fei Li, Xutong Li, Lifan Chen, Xiaozhe Wan, Xiaohong Liu, Tianbiao Yang, Xiaochu Tong, Tingyang Xu, Rongrong Cui, Hualiang Jiang, Sulin Zhang, Hong Liu, Mingyue Zheng
Abstract
Alterations of discoidin domain receptor1 (DDR1) may lead to increased production of inflammatory cytokines, making DDR1 an attractive target for inflammatory bowel disease (IBD) therapy. A scaffold-based molecular design workflow was established and performed by integrating a deep generative model, kinase selectivity screening and molecular docking, leading to a novel DDR1 inhibitor compound 2, which showed potent DDR1 inhibition profile (IC50 = 10.6 ± 1.9 nM) and excellent selectivity against a panel of 430 kinases (S (10) = 0.002 at 0.1 μM). Compound 2 potently inhibited the expression of pro-inflammatory cytokines and DDR1 autophosphorylation in cells, and it also demonstrated promising oral therapeutic effect in a dextran sulfate sodium (DSS)-induced mouse colitis model.