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

文献类型：期刊论文

作者Tan, Xiaoqin4,5; Li, Chunpu6,7; Yang, Ruirui4,8,9,10; Zhao, Sen6; Li, Fei1; Li, Xutong4,8; Chen, Lifan4,8; Wan, Xiaozhe4,8; Liu, Xiaohong4,9,10; Yang, Tianbiao4,7
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-01-13
卷号65期号:1页码:103-119
ISSN号0022-2623
DOI10.1021/acs.jmedchem.1c01205
通讯作者Zhang, Sulin(slzhang@simm.ac.cn) ; Liu, Hong(hliu@simm.ac.cn) ; Zheng, Mingyue(myzheng@simm.ac.cn)
英文摘要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.
WOS关键词DOMAIN RECEPTOR 1 ; INFLAMMATORY-BOWEL-DISEASE ; DISCOIDIN ; KINASE ; INVASION ; CYTOKINES ; MICE
资助项目National Natural Science Foundation of China[81773634] ; National Natural Science Foundation of China[21632008] ; National Natural Science Foundation of China[81903639] ; Shanghai Municipal Science and Technology Major Project ; Tencent AI Lab Rhino-Bird Focused Research Program[JR202002] ; Shanghai Sailing Program[19YF1457800] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Science and Technology Commission of Shanghai Municipality[18JC1411304] ; SA-SIBS Scholarship Program ; Youth Innovation Promotion Association CAS[2020282]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000766544600007
源URL[http://119.78.100.183/handle/2S10ELR8/300179]  
专题新药研究国家重点实验室
通讯作者Zhang, Sulin; Liu, Hong; Zheng, Mingyue
作者单位1.Fudan Univ, Shanghai 200433, Peoples R China
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
3.Tencent AI Lab, Shenzhen 518057, Peoples R China
4.Chinese Acad Sci, Bel aDrug Discovery & Design Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.ByteDance AI Lab, Shanghai 201103, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, El bState Key Lab Drug Res, Shanghai 201203, Peoples R China
7.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
8.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
9.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 200031, Peoples R China
10.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China
推荐引用方式
GB/T 7714		 Tan, Xiaoqin,Li, Chunpu,Yang, Ruirui,et al. Discovery of Pyrazolo[3,4-d]pyridazinone Derivatives as Selective DDR1 Inhibitors via Deep Learning Based Design, Synthesis, and Biological Evaluation[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022,65(1):103-119.
APA Tan, Xiaoqin.,Li, Chunpu.,Yang, Ruirui.,Zhao, Sen.,Li, Fei.,...&Zheng, Mingyue.(2022).Discovery of Pyrazolo[3,4-d]pyridazinone Derivatives as Selective DDR1 Inhibitors via Deep Learning Based Design, Synthesis, and Biological Evaluation.JOURNAL OF MEDICINAL CHEMISTRY,65(1),103-119.
MLA Tan, Xiaoqin,et al."Discovery of Pyrazolo[3,4-d]pyridazinone Derivatives as Selective DDR1 Inhibitors via Deep Learning Based Design, Synthesis, and Biological Evaluation".JOURNAL OF MEDICINAL CHEMISTRY 65.1(2022):103-119.

入库方式： OAI收割

来源：上海药物研究所

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