Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFRL858R/T790M/C797S)

Autor:	Su-Jie Zhu, Hua Xie, Wei Xu, Ke Ding, Sun Min, Cai-Hong Yun, Xiaoyun Lu, Jiayi Shen, Rong Zhang, Tao Zhang, Linjiang Tong, Jian Ding, Mengzhen Lai, Ruibo Wu
Rok vydání:	2019
Předmět:	Mutation biology Chemistry Mutant Wild type medicine.disease medicine.disease_cause respiratory tract diseases T790M Drug Discovery Cancer research biology.protein medicine Molecular Medicine Structure–activity relationship Osimertinib Epidermal growth factor receptor Lung cancer
Zdroj:	Journal of Medicinal Chemistry. 62:7302-7308
ISSN:	1520-4804 0022-2623
DOI:	10.1021/acs.jmedchem.9b00576
Popis:	Tertiary EGFRC797S mutation induced resistance against osimertinib (1) is an emerging "unmet clinical need" for non-small-cell lung cancer (NSCLC) patients. A series of 5-methylpyrimidopyridone derivatives were designed and synthesized as new selective EGFRL858R/T790M/C797S inhibitors. A representative compound, 8r-B, exhibited an IC50 of 27.5 nM against the EGFRL858R/T790M/C797S mutant, while being a significantly less potent for EGFRWT (IC50 > 1.0 μM). Cocrystallographic structure determination and computational investigation were conducted to elucidate its target selectivity.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::91ed1233b1c43c61931039b300127de8 https://doi.org/10.1021/acs.jmedchem.9b00576 Zobrazit plný text záznamu