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Design, synthesis and biological evaluation of AZD9291 derivatives as selective and potent EGFRL858R/T790M inhibitors
- Source :
- European Journal of Medicinal Chemistry. 163:367-380
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- Third-generation epidermal growth factor receptor (EGFR)L858R/T790M inhibitors are still the main drugs for the treatment of advanced non-small cell lung cancer (NSCLC), and these drugs have achieved remarkable clinical efficacy. However, there are still many patients suffering from drug-resistant mutations and drug side effects caused by NSCLC. In this study, guided by the molecular simulation, we applied a structure-based drug design strategy (SBDD) and optimized the structure to obtain a series of potent and selective EGFRL858R/T790M inhibitors. The most potent compound 18e demonstrated excellent kinase inhibitory activity and selectivity for EGFRL858R/T790M double mutants and the IC50 value reached nanomolar level. The selectivity of 18e against wild-type EGFR was near to 200-fold. In addition, compound 18e also inhibited H1975 cells proliferation at G2/M phase and induced apoptosis at a concentration of 0.25 μM, which makes it more valuable for potential lung cancer research.
- Subjects :
- Drug
media_common.quotation_subject
Mutant
01 natural sciences
03 medical and health sciences
T790M
Drug Discovery
medicine
Epidermal growth factor receptor
Lung cancer
IC50
030304 developmental biology
media_common
Pharmacology
0303 health sciences
biology
010405 organic chemistry
Kinase
Chemistry
Organic Chemistry
General Medicine
medicine.disease
respiratory tract diseases
0104 chemical sciences
Apoptosis
Cancer research
biology.protein
Subjects
Details
- ISSN :
- 02235234
- Volume :
- 163
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi...........0d914ab40b3d3e0ebb16d51d24725b77