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Identification of Pyridinyltriazine Derivatives as Potent panFGFR Inhibitors against Gatekeeper Mutants for Overcoming Drug Resistance

Authors
 SeongShick Ryu  ;  Yunju Nam  ;  Namkyoung Kim  ;  Injae Shin  ;  Eunhye Jeon  ;  Younghoon Kim  ;  Nam Doo Kim  ;  Taebo Sim 
Citation
 JOURNAL OF MEDICINAL CHEMISTRY, Vol.65(8) : 6017-6038, 2022-04 
Journal Title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN
 0022-2623 
Issue Date
2022-04
MeSH
Animals ; Antineoplastic Agents* / pharmacology ; Antineoplastic Agents* / therapeutic use ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Drug Resistance ; Humans ; Mice ; Protein Kinase Inhibitors* / pharmacology ; Protein Kinase Inhibitors* / therapeutic use ; Signal Transduction
Abstract
Although FGFR inhibitors hold promise in treating various cancers, resistance to the FGFR inhibitors caused by acquired secondary mutations has emerged. To discover novel FGFR inhibitors capable of inhibiting FGFR mutations, including gatekeeper mutations, we designed and synthesized several new pyridinyltriazine derivatives. A structure-activity relationship (SAR) study led to the identification of 17a as a highly potent panFGFR inhibitor against wild-type and mutant FGFRs. Notably, 17a is superior to infigratinib in terms of kinase-inhibitory and cellular activities, especially against V555M-FGFR3. Molecular dynamics simulations provide a clear understanding of why pyridinyltraizine derivative 17a possesses activity against V555M-FGFR3. Moreover, 17a significantly suppresses proliferation of cancer cells harboring FGFR mutations via FGFR signaling blockade, cell cycle arrest, and apoptosis. Furthermore, 17a and 17b exhibited remarkable efficacies in TEL-V555M-FGFR3 Ba/F3 xenograft mouse model and 17a is more efficacious than infigratinib. This study provides new insight into the design of novel FGFR inhibitors that are active against FGFR mutants.
Full Text
https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01776
DOI
10.1021/acs.jmedchem.1c01776
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Sim, Taebo(심태보)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/188578
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