Targeting acute myeloid leukemia with a small molecule inhibitor of the Myb/p300 interaction

Uttarkar S, Dassé E, Coulibaly A, Steinmann S, Jakobs A, Schomburg C, Trentmann A, Jose J, Schlenke P, Berdel WE, Schmidt TJ, Müller-Tidow C, Trampton J, Klempnauer KH

Abstract

The transcription factor Myb plays a key role in the hematopoietic system and has beenimplicated in the development of leukemia and other human cancers. Inhibition of Myb istherefore emerging as a potential therapeutic strategy for these diseases. However, due tolack of suitable inhibitors the feasibility of therapeutic approaches based on Myb inhibitionhas not been explored. We have identified the triterpenoid Celastrol as a potent lowmolecularweight inhibitor of the interaction of Myb with its cooperation partner p300. Wedemonstrate that Celastrol suppresses the proliferative potential of acute myeloid leukemia(AML) cells while not affecting normal hematopoietic progenitor cells. Furthermore, Celastrolprolongs the survival of mice in a model of an aggressive AML. Overall, our workdemonstrates the therapeutic potential of a small-molecule inhibitor of the Myb/p300interaction for the treatment of AML and provides a starting point for the further developmentof Myb-inhibitory compounds for the treatment of leukemia and, possibly, other tumors drivenby deregulated Myb.