Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 30, Issue 16, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2020.127327
Keywords
EGFR; NSCLC; C797S
Categories
Funding
- National Key Research and Development Program [2016YFA0502304]
- National Natural Science Foundation of China [81825020]
- National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China [2018ZX09711002]
- Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase) [U1501501]
- National Program for Special Supports of Eminent Professionals
- National Program for Support of Top-Notch Young Professionals
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The efficacy of EGFR inhibitors is frequently affected by acquired resistance. EGFR(19D/T790M/C797S) mutation is one of the primary reasons for the emergence of resistance after treatment with the third-generation EGFR inhibitors such as AZD9291, CO1686 and Olmutinib. To overcome the resistance mutation 19D/T790M/C797S, we designed and prepared a series of indole derivatives with the terminal hydroxyl of alkyl chain to increase extra interaction with the Asp855 in the conservative DFG site. Activity evaluation, structure-activity relationship and docking analysis were also carried out. Among them, compound 12e displayed significant inhibitory activity against EGFR(19D/T790M/C797S) (IC50 = 15.3 nM) and good selectivity over EGFR WT (IC50 > 1000 nM), L858R/T790M (IC50, 156.6 nM) and L858R/T790M/C797S (IC50, 218.3 nM) respectively. Furthermore, 12e exhibited good growth inhibition activity, induced G1 phase cell cycle arrest and apoptosis in BaF3/EGFR(19D/T790M/C797S) cells by suppressing EGFR phosphorylation signaling pathway. In all, our study might provide a novel structural design method and lay the solid foundation for the development of the 4th generation EGFR(19D/T790M/C797S) inhibitors.
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