AI-10-49

AI-10-49 is an inhibitor that binds the transcription factor fusion CBFβ-SMMHC. AI-10-49, that selectively binds to CBFβ-SMMHC and disrupts its binding to RUNX1. AI-10-49 restores RUNX1 transcriptional activity, displays favorable pharmacokinetics, and delays leukemia progression in mice. Treatment of primary inv (16) AML patient blasts with AI-10-49 triggers selective cell death. These data suggest that direct inhibition of the oncogenic CBFβ-SMMHC fusion protein may be an effective therapeutic approach for inv (16) AML, and they provide support for transcription factor targeted therapy in other cancers. (In Vitro) :AI-10-49 inhibits the binding of CBFβ-SMMHCto theRUNX1 Runt domain with IC50 value of 0.26 μM.AI-10-49 (1 μM; 3, 6, 12 hours) has selectivity for inhibiting CBFβ-SMMHC binding to RUNX1. (In Vivo) :AI-10-49 (200 mg/kg; per day) delays leukemia progression in mice.