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Discovery and optimization of a series of 3-substituted indazole derivatives as multi-target kinase inhibitors for the treatment of lung squamous cell carcinoma
- Source :
- European Journal of Medicinal Chemistry. 163:671-689
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
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.
- 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
Subjects
Details
- ISSN :
- 02235234
- Volume :
- 163
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....f853a4678d669eb5f71c6567558f5d0d