Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 10, Issue 6, Pages 869-873Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.8b00564
Keywords
EGFR; mutant; inhibitor; C797S
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Funding
- National Key Research and Development Program [2016YFA0502304]
- National Natural Science Foundation of China [81825020, 81803437]
- National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China [2018ZX09711002]
- Fundamental Research Funds for the Central Universities
- Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund [U1501501]
- Shanghai Sailing Program [18YF1405100]
- National Program for Special Support of Eminent Professionals
- National Program for Support of Top-notch Young Professionals
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In this paper, we describe the discovery and optimization of a series of noncovalent reversible epidermal growth factor receptor inhibitors of EGFR(L858R/T790M/C797S). One of the most promising compounds, 25g, inhibited the enzymatic activity of EGFR(L8S8R/T790M/C797S) with an IC50 value of 2.2 nM. Cell proliferation assays showed that 25g effectively and selectively inhibited the growth of EGFR(L858R/T790M/C797S)-dependent cells. This series of compounds, which occupy both the ATP binding site and the allosteric site of the EGFR kinase, may serve as a basis for the development of fourth-generation EGFR inhibitors for L858R/T790M/C797S mutants.
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