BLU-654

BLU-654 is an orally active antitumor agent and KIT inhibitor. It targets wild-type KIT, PDGFRβ, and serves as a highly selective inhibitor of KITV654A among most other kinases in the kinome. BLU-654 demonstrates sustained antitumor activity in xenograft mouse models derived from KITV654A cells. It is applicable for research related to Imatinib-resistant gastrointestinal stromal tumors.

BLU-654 potently inhibits the autophosphorylation of KIT in HMC1.1 11/13 cells with an IC50 of 5.7 nM. It also inhibits the autophosphorylation of wild-type KIT in M-07e cells, showing an IC50 of 82.7 nM and exhibits a 15-fold higher selectivity for KIT V654A compared to wild-type KIT. In SW569 cells, BLU-654 inhibits PDGFRβ autophosphorylation with an IC50 of 1251.4 nM and demonstrates 219-fold higher selectivity for KIT V654A relative to PDGFRβ. BLU-654 shows species-dependent metabolic stability, with no intrinsic clearance in human and canine liver microsomes, while displaying lower clearance in human hepatocytes (2 mL·min −1 ·kg −1 ) and higher clearance rates in rat, dog, and cynomolgus monkey hepatocytes.

BLU-654 (1-60 mg/kg; oral administration; once daily for 27 days) exhibits a potent and dose-dependent inhibition of pSTAT5 (a downstream marker of KIT activity) in HMC1.1 11/13 xenografts.