期刊
BULLETIN OF THE KOREAN CHEMICAL SOCIETY
卷 43, 期 8, 页码 1032-1036出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/bkcs.12578
关键词
EGFR; EGFR L858R/T790M/C797S; EGFR L858R/T790M; tyrosine kinase inhibitor; 3 ',4 ',5 '-trihydroxyphenylbenzamide
资金
- Basic Research Laboratory Program (BRL) of the Korean National Research Foundation - Korean Ministry of Science, ICT and Future Planning [NRF-2020R1A4A1016142]
The research team designed and synthesized 16 analogs of EGFR mutant inhibitors, identifying 9a, 9b, and 20b as inhibitors for EGFR L858R/T790M/C797S mutations, and 10a and 10b as inhibitors for multiple mutation types. Additionally, a molecular docking study on a plausible binding mode of the compounds was provided.
Development of a mutant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor is important for the treatment of various cancers. Third-generation EGFR tyrosine kinase inhibitors (TKIs) have been clinically used by targeting T790M specifically but are recently known to induce T790M/C797S mutation after the treatment. Therefore, there is an unmet need to develop novel kinase inhibitors targeting the mutant EGFRs. Here, we designed and synthesized 16 analogs by hybridizing EAI045 (1) and 3',4',5'-trihydroxyflavone (2) and identified 9a, 9b, and 20b as EGFR L858R/T790M/C797S mutant inhibitors. In addition, we found that 10a and 10b can inhibit both L858R/T790M and L858R/1790M/C797S. Molecular docking study on a plausible binding mode of the compounds is also provided.
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