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2-amino-2, 3-dihydro-1h-indene-5-carboxamide-based discoidin domain receptors 1 (DDR1) inhibitors: design, synthesis, and in vivo anti-pancreatic cancer efficacy

DOI: 10.1021/acs.jmedchem.9b00365 DOI Help

Authors: Dongsheng Zhu (Jinan University; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences) , Huocong Huang (UT Southwestern) , Daniel Pinkas (Structural Genomics Consortium, University of Oxford) , Jinfeng Luo (Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences) , Debolina Ganguly (Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences) , Alice E. Fox (Structural Genomic Consortium, University of Oxford) , Emily Arner (Structural Genomics Consortium, University of Oxford) , Qiuping Xiang (UT Southwestern) , Zheng-chao Tu (Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences) , Alex N. Bullock (Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences) , Rolf A Brekken (UT Southwestern) , Ke Ding (Jinan University) , Xiaoyun Lu (Jinan University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: July 2019
Diamond Proposal Number(s): 15433

Abstract: Pancreatic cancer is a leading cause of cancer-related death. A series of 2-amino-2, 3-dihydro-1H-indene-5-carboxamide derivatives were designed and synthesized as novel selective DDR1 inhibitors to exhibit promising in vitro and in vivo anti-pancreatic cancer activity. One of the representative compounds, 7f, binds with DDR1 with a Kd value of 5.9 nM and suppresses the kinase activity with an IC50 value of 14.9 nM, but is significantly less potent for majority of a panel of 403 wild-type kinases. The compound potently inhibited collagen-induced epithelial-mesenchymal transition (EMT) and dose-dependently suppressed colony formation of pancreatic cancer cells. Furthermore, 7f also demonstrated reasonable pharmacokinetic profiles and displayed promising in vivo therapeutic efficacy in an orthotopic mouse model of pancreatic cancer. Compound 7f may serve as a new lead compound for future drug discovery.

Subject Areas: Chemistry, Medicine


Instruments: I04-Macromolecular Crystallography