Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFRL858R/T790M/C797S).
Jiayi ShenTao ZhangSu-Jie ZhuMin SunLinjiang TongMengzhen LaiRong ZhangWei XuRuibo WuJian DingCai-Hong YunHua XieXiaoyun LuKe DingPublished in: Journal of medicinal chemistry (2019)
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.
Keyphrases
- epidermal growth factor receptor
- wild type
- advanced non small cell lung cancer
- small cell lung cancer
- tyrosine kinase
- end stage renal disease
- ejection fraction
- newly diagnosed
- chronic kidney disease
- prognostic factors
- peritoneal dialysis
- photodynamic therapy
- cross sectional
- oxidative stress
- diabetic rats
- mass spectrometry
- solid phase extraction
- robot assisted
- drug induced
- liquid chromatography
- molecularly imprinted