Discovery of Pyrazolo[3,4-d]pyridazinone Derivatives as Selective DDR1 Inhibitors via Deep Learning Based Design, Synthesis, and Biological Evaluation
Discovery of Pyrazolo[3,4-d]pyridazinone Derivatives as Selective DDR1 Inhibitors via Deep Learning Based Design, Synthesis, and Biological Evaluation
复制标题
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
DOI：
10.1021/acs.jmedchem.1c01205
复制
发表时间：
2022-01-13
影响因子：
7.3
通讯作者：
Zheng, Mingyue
中科院分区：
文献类型：
--
作者：
Tan, Xiaoqin;Li, Chunpu;Zheng, Mingyue
盘状结构域受体1（DDR 1）的改变可能导致炎性细胞因子的产生增加，使得DDR 1成为炎性肠病（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，得到了新的DDR 1抑制剂化合物2，其显示出有效的DDR 1抑制曲线（IC 50 = 10.6 +/- 1.9 nM）和对一组430种激酶的优异选择性（在0.1 μ M时S（10）= 0.002）。化合物2有效地抑制细胞中促炎细胞因子的表达和DDR 1自磷酸化，并且其还在葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎模型中显示出有希望的口服治疗效果。
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 mu M). 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.