Dual SLC25A51 and SDHA inhibitor 615 is a specific small molecule dual inhibitor of SLC25A51 and succinate dehydrogenase (SDH) subunit SDHA, selectively kills KRAS-mutated cells.
615 is a highly selective agent that effectively kills iKRAS cells under both unstressed and Gal-stressed conditions.
615 demonstrates the broad efficacy and selectivity of 615 across KRAS-mutated cell types, including NOMO-1 cells, NH-KRAS cells, KRAS-mutated AML patient samples, and KRAS-mutated solid tumor cells.
615 exerts its cytotoxic effects through mechanisms distinct from direct KRAS inhibition.
615 significantly reduced the in vivo engraftment of iKRAS cells, NOMO-1 cells, NH-KRAS cells.
615 (12.5 mg/kg intraperitoneally) prolonged the survival of KRAS-mutated leukemic mice.
615 binds to SDHA and impairs its enzymatic function, reduces OXPHOS via binding to SDHA, contributing to its selective toxicity toward KRAS-mutated cells.
615 selectively depletes mito NAD+ in KRAS-mutated cells via inhibiting SLC25A51.
615 directly binds to SLC25A51 (MST KD=0.344 uM) to inhibit mito NAD+ import.