Nam, Yunju Kim, Chan Han, Junghee Ryu Seong-Shick Cho, Hanna Song, Chiman Kim, Nam Doo Kim, Namkyoung Sim, Taebo 2024-01-12T02:33:36Z 2024-01-12T02:33:36Z 2023-01-04 2023-01 2072-6694 https://pubs.kist.re.kr/handle/201004/75861 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. English Multidisciplinary Digital Publishing Institute (MDPI) Identification of Thiazolo[5,4-b]pyridine Derivatives as c-KIT Inhibitors for Overcoming Imatinib Resistance Article 10.3390/cancers15010143 1 Cancers, v.15, no.1 Cancers 15 1 Y scie scopus 000910414700001 Oncology Oncology Article GASTROINTESTINAL STROMAL TUMORS TYROSINE KINASE CELL-LINE GATEKEEPER MUTANT MUTATIONS RECEPTOR DISCOVERY ACTIVATION MECHANISMS SUNITINIB c-KIT GIST GIST-T1 HMC1 2 imatinib resistance thiazolo[5 4-b]pyridine