Discovery of Pyrazolo[3,4-]pyridazinone Derivatives as Selective DDR1 Inhibitors via Deep Learning Based Design, Synthesis, and Biological Evaluation.

Journal: Journal of medicinal chemistry
PMID: 34821145

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 , which showed potent DDR1 inhibition profile (IC = 10.6 ± 1.9 nM) and excellent selectivity against a panel of 430 kinases ( (10) = 0.002 at 0.1 μM). Compound 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.

Authors

  • Xiaoqin Tan
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Chunpu Li
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • Ruirui Yang
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • Sen Zhao
    College of Information and Computer, Taiyuan University of Technology, Taiyuan 030024, China.
  • Fei Li
    Institute for Precision Medicine, Tsinghua University, Beijing, China.
  • Xutong Li
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Lifan Chen
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Xiaozhe Wan
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • Xiaohong Liu
    Department of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang 110016, China. Electronic address: lvj221@163.com.
  • Tianbiao Yang
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • Xiaochu Tong
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • Tingyang Xu
    University of Connecticut.
  • Rongrong Cui
    School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China.
  • Hualiang Jiang
    Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China ; School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
  • Sulin Zhang
  • Hong Liu
    Key Laboratory of Grain and Oil Processing and Food Safety of Sichuan Province, College of Food and Bioengineering, Xihua University Chengdu 610039 China xingyage1@163.com.
  • Mingyue Zheng
    School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, Zhejiang Province, China.

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