Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFR L858R/T790M/C797S )

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 EGFR(L858R/T790M/C797S) inhibitors. A...

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Published inJournal of medicinal chemistry Vol. 62; no. 15; pp. 7302 - 7308
Main Authors Shen, Jiayi, Zhang, Tao, Zhu, Su-Jie, Sun, Min, Tong, Linjiang, Lai, Mengzhen, Zhang, Rong, Xu, Wei, Wu, Ruibo, Ding, Jian, Yun, Cai-Hong, Xie, Hua, Lu, Xiaoyun, Ding, Ke
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 08.08.2019
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
LUNG-CANCER
EGFR INHIBITORS
GEFITINIB
RESISTANCE
OPTIMIZATION
MUTATIONS
DISCOVERY
AZD9291
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Summary: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 EGFR(L858R/T790M/C797S) inhibitors. A representative compound, 8r-B, exhibited an ICso of 27.5 nM against the EGFR(L858R/T790M/C797S) mutant, while being a significantly less potent for EGFRwr (IC50 > 1.0 NM). Cocrystallographic structure determination and computational investigation were conducted to elucidate its target selectivity.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.9b00576