SBI-0206965 #29089

SBI-0206965 is a potent, selective and cell permeable inhibitor of the autophagy-promoting serine/threonine kinase ULK1 (1). ULK1 is an essential protein for induction of autophagy by nutrient starvation and mTOR inhibition (2). ULK1 is recripocally regulated by multple phosphorylation sites via AMPK and mTOR, such that ULK1 is activated by AMPK and inhibited by mTOR (3, 4). By in vitro kinase assays, SBI-0206965 inhibits ULK1 with an IC₅₀ of 108 nM and to a lesser extent ULK2 with an IC₅₀ of 711 nM (1). In a panel of 456 kinases, when tested at 10 μM, SBI-0206965 showed remarkable selectivity and only inhibited 10 kinases, including ULK1 and ULK2. Other kinase that were inhibited included FAK, FLT3, Src, and Jak3. Only FLT3 and FAK had an IC₅₀ similar to ULK1 when tested in in vitro kinase assays. SBI-020695 inhibits survival following nutrient deprivation. Furthermore, SBI-0206965 inhibits autophagy induced by mTOR inhibition and converts the cytostatic response to mTOR inhibition to a cytotoxic apoptotic response.