Discovery and optimization of a series of 3-substituted indazole derivatives as multi-target kinase inhibitors for the treatment of lung squamous cell carcinoma

• Published in: European journal of medicinal chemistry 2019-02, Vol.163, p.671-689
• Main Authors: Wang, Qi, Dai, Yang, Ji, Yinchun, Shi, Huanyu, Guo, Zuhao, Chen, Danqi, Chen, Yuelei, Peng, Xia, Gao, Yinglei, Wang, Xin, Chen, Lin, Jiang, Yuchen, Geng, Meiyu, Shen, Jingkang, Ai, Jing, Xiong, Bing
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - enzymology; DDR; Discoidin Domain Receptor 2 - antagonists & inhibitors; Drug Discovery; FGFR; Heterografts; Humans; Indazoles - chemical synthesis; Indazoles - chemistry; Indazoles - pharmacology; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Mice; Multi-target inhibitor; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - therapeutic use; Receptor, Fibroblast Growth Factor, Type 1 - antagonists & inhibitors; Squamous cell carcinoma; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.12.015

Although lung adenocarcinoma patients have benefited from the development of targeted therapy, patients with lung squamous cell carcinoma (SqCC) have no effective treatment due to the complexity and heterogeneity of the disease. Therefore, basing on the genetic analysis of mutations in lung squamous cell carcinoma to design multi-target inhibitors represents a potential strategy for the medical treatment. In this study, through screening an in-house focused library, we identified an interesting indazole scaffold. And following with binding analysis, we elaborated the structure-activity relationship of this hit compound by optimizing four parts guided by the DDR2 enzymatic assay, which resulted in a potent lead compound 10a. We conducted further optimization of dual enzymatic inhibitions towards FGFR1 and DDR2, two important kinases in lung squamous cell carcinoma. Finally, from the cellular antiproliferative activity tests and in vivo pharmacokinetic test, 3-substituted indazole derivative 11k was found to be a promising candidate and subjected to in vivo pharmacology study with the mouse xenograft models, demonstrating profound anti-tumor efficacy. Additional in vitro druglike assessment reinforced that compound 11k could be valuable for SqCC drug development. [Display omitted] •Lung Squamous Cell Carcinoma is a complex disease and involves multi-target abnormality.•Kinase focused library was used to identify indazole scaffold for developing multi-target inhibitors.•Promising candidate was selected with the balance of enzymatic potency, antiproliferative inhibition and DMPK.•In vivo PK and pharmacology studies confirmed the potential of compound 11k for further development.