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.

中文翻译：

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通过基于深度学习的设计、合成和生物学评估发现吡唑并[3,4-d]哒嗪酮衍生物作为选择性 DDR1 抑制剂

盘状结构域受体 1 (DDR1) 的改变可能导致炎性细胞因子的产生增加，使 DDR1 成为炎症性肠病 (IBD) 治疗的有吸引力的靶点。通过整合深度生成模型、激酶选择性筛选和分子对接，建立并执行了基于支架的分子设计工作流程，从而产生了一种新型 DDR1 抑制剂化合物2，该化合物显示出有效的 DDR1 抑制曲线 (IC ₅₀ = 10.6 ± 1.9 nM) 和对一组 430 种激酶具有出色的选择性（S (10) = 0.002，0.1 μM）。化合物2有效抑制细胞中促炎细胞因子的表达和 DDR1 自磷酸化，并且在葡聚糖硫酸钠 (DSS) 诱导的小鼠结肠炎模型中也显示出有希望的口服治疗效果。