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Eur J Med Chem. 2019 Feb 1;163:671-689. doi: 10.1016/j.ejmech.2018.12.015. Epub 2018 Dec 7.

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 information

1
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing, 100049, China.
2
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
3
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
4
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing, 100049, China.
5
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing, 100049, China. Electronic address: jai@simm.ac.cn.
6
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing, 100049, China. Electronic address: bxiong@simm.ac.cn.

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.

KEYWORDS:

DDR; FGFR; Multi-target inhibitor; Squamous cell carcinoma

PMID:
30572178
DOI:
10.1016/j.ejmech.2018.12.015
[Indexed for MEDLINE]

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