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

SIMPLE SUMMARY: c-KIT has been regarded as a promising therapeutic target against gastrointestinal stromal tumor (GIST). Overcoming drug resistance of c-KIT inhibitors including imatinib is required. We designed and synthesized novel thiazolo[5,4-b]pyridine derivatives and performed structure-activity relationship (SAR) studies to overcome imatinib resistance. The SAR studies led to the identification of the derivative 6r as a potent c-KIT inhibitor. The derivative 6r is capable of strongly inhibiting a c-KIT V560G/D816V double mutant that is resistant to imatinib and remarkably attenuates proliferation of GIST-T1 and HMC1.2 cancer cells. Moreover, 6r possesses differential cytotoxicity on c-KIT D816V Ba/F3 cells relative to parental Ba/F3 cells. Kinase panel profiling revealed that 6r has reasonable kinase selectivity. Furthermore, 6r not only blocks migration and invasion, but also suppresses anchorage-independent growth of GIST-T1 cells. 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.