1. Discovery and optimization of a series of 3-substituted indazole derivatives as multi-target kinase inhibitors for the treatment of lung squamous cell carcinoma
- Author
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Xia Peng, Meiyu Geng, Qi Wang, Xin Wang, Lin Chen, Yuchen Jiang, Zuhao Guo, Yue-Lei Chen, Yinglei Gao, Danqi Chen, Yang Dai, Huanyu Shi, Jingkang Shen, Yinchun Ji, Bing Xiong, and Jing Ai
- Subjects
Indazoles ,Lung Neoplasms ,medicine.medical_treatment ,Antineoplastic Agents ,01 natural sciences ,Targeted therapy ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Discoidin Domain Receptor 2 ,Drug Discovery ,medicine ,Animals ,Humans ,Receptor, Fibroblast Growth Factor, Type 1 ,Protein Kinase Inhibitors ,030304 developmental biology ,Pharmacology ,chemistry.chemical_classification ,0303 health sciences ,Indazole ,010405 organic chemistry ,Kinase ,Fibroblast growth factor receptor 1 ,Organic Chemistry ,General Medicine ,medicine.disease ,0104 chemical sciences ,Enzyme ,chemistry ,Drug development ,Fibroblast growth factor receptor ,Carcinoma, Squamous Cell ,Cancer research ,Heterografts ,Adenocarcinoma - Abstract
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.
- Published
- 2019