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Identification of Thiazolo[5,4- b]pyridine Derivatives as c-KIT Inhibitors for Overcoming Imatinib Resistance

Authors
 Yunju Nam  ;  Chan Kim  ;  Junghee Han  ;  SeongShick Ryu  ;  Hanna Cho  ;  Chiman Song  ;  Nam Doo Kim  ;  Namkyoung Kim  ;  Taebo Sim 
Citation
 CANCERS, Vol.15(1) : 143, 2023-01 
Journal Title
CANCERS
Issue Date
2023-01
Keywords
GIST ; GIST-T1 ; HMC1.2 ; c-KIT ; imatinib resistance ; thiazolo[5,4-b]pyridine
Abstract
c-KIT is a promising therapeutic target against gastrointestinal stromal tumor (GIST). In order to identify novel c-KIT inhibitors capable of overcoming imatinib resistance, we synthesized 31 novel thiazolo[5,4-b]pyridine derivatives and performed SAR studies. We observed that, among these substances, 6r is capable of inhibiting significantly c-KIT and suppressing substantially proliferation of GIST-T1 cancer cells. It is of note that 6r is potent against a c-KIT V560G/D816V double mutant resistant to imatinib. Compared with sunitinib, 6r possesses higher differential cytotoxicity on c-KIT D816V Ba/F3 cells relative to parental Ba/F3 cells. In addition, kinase panel profiling reveals that 6r has reasonable kinase selectivity. It was found that 6r remarkably attenuates proliferation of cancer cells via blockade of c-KIT downstream signaling, and induction of apoptosis and cell cycle arrest. Furthermore, 6r notably suppresses migration and invasion, as well as anchorage-independent growth of GIST-T1 cells. This study provides useful SAR information for the design of novel c-KIT inhibitors overcoming imatinib-resistance.
Files in This Item:
T202300205.pdf Download
DOI
10.3390/cancers15010143
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Sim, Taebo(심태보)
Cho, Hanna(조한나)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/192950
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