Discovery of Novel 5,6-Dihydro-4 H -pyrido[2,3,4- de ]quinazoline Irreversible Inhibitors Targeting Both Wild-Type and A775_G776insYVMA Mutated HER2 Kinases.

Autor:	Yang L; College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China.; . Beijing Scitech MQ Pharmaceuticals Ltd., Beijing 101320, China., Li Y; College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China., Du Y; . Beijing Scitech MQ Pharmaceuticals Ltd., Beijing 101320, China., Guo Y; . Beijing Scitech MQ Pharmaceuticals Ltd., Beijing 101320, China., Guo Z; . Beijing Scitech MQ Pharmaceuticals Ltd., Beijing 101320, China., Liu B; . Beijing Scitech MQ Pharmaceuticals Ltd., Beijing 101320, China., Liu J; . Beijing Scitech MQ Pharmaceuticals Ltd., Beijing 101320, China., Liu Y; . Beijing Scitech MQ Pharmaceuticals Ltd., Beijing 101320, China., Niu H; . Beijing Scitech MQ Pharmaceuticals Ltd., Beijing 101320, China., Sun Y; . Beijing Scitech MQ Pharmaceuticals Ltd., Beijing 101320, China., Yan H; . Beijing Scitech MQ Pharmaceuticals Ltd., Beijing 101320, China., Yang Y; . Beijing Scitech MQ Pharmaceuticals Ltd., Beijing 101320, China., Yu S; . Beijing Scitech MQ Pharmaceuticals Ltd., Beijing 101320, China., Zhang Y; . Beijing Scitech MQ Pharmaceuticals Ltd., Beijing 101320, China., Zhang Y; . Beijing Scitech MQ Pharmaceuticals Ltd., Beijing 101320, China., Zheng K; . Beijing Scitech MQ Pharmaceuticals Ltd., Beijing 101320, China., Zheng N; . Beijing Scitech MQ Pharmaceuticals Ltd., Beijing 101320, China., Zhang X; . Beijing Scitech MQ Pharmaceuticals Ltd., Beijing 101320, China., Zhang Q; . Beijing Scitech MQ Pharmaceuticals Ltd., Beijing 101320, China., Hu L; College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China.; Beijing Key Laboratory of Environmental and Viral Oncology, Beijing 100124, China.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Apr 11; Vol. 67 (7), pp. 5662-5682. Date of Electronic Publication: 2024 Mar 22.
DOI:	10.1021/acs.jmedchem.3c02302
Abstrakt:	HER2 mutations were seen in 4% of non-small-cell lung cancer (NSCLC) patients. Most of these mutations (90%) occur as an insertion mutation within the exon 20 frame, leading to the downstream activation of the PI3K-AKT and RAS/MAPK pathways. However, no targeted therapies have yet been approved worldwide. Here a novel series of highly potent HER2 inhibitors with a pyrido[2,3,4- de ]quinazoline core were designed and developed. The derivatives with the pyrido[2,3,4- de ]quinazoline core displayed superior efficacy of antiproliferation in BaF3 cells harboring HER2insYVMA mutation compared with afatinib and neratinib. Rat studies showed that 8a and 9a with the newly developed core have good pharmacokinetic properties with an oral bioavailability of 41.7 and 42.0%, respectively. Oral administration of 4a and 10e (30 mg/kg, QD) displayed significant antitumor efficacy in an in vivo xenograft model. We proposed promising strategies for the development of HER2insYVMA mutant inhibitors in this study.
Databáze:	MEDLINE
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