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Blood. 2016 Mar 3;127(9):1173-82. doi: 10.1182/blood-2015-09-668632. Epub 2015 Dec 2.

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

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Institute for Biochemistry and Graduate School of Chemistry, University of Münster, Münster, Germany;
Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom;
Institute for Biochemistry and.
Institute for Pharmaceutical Biology and Phytochemistry and.
Institute for Pharmaceutical and Medicinal Chemistry, University of Münster, Münster, Germany;
Institute for Transfusion Medicine, University Hospital, University of Graz, Graz, Austria;
Department of Medicine A, Hematology and Oncology, University Hospital, University of Münster, Münster, Germany; and.
Department of Medicine, Hematology and Oncology, University of Halle, Halle, Germany.


The transcription factor Myb plays a key role in the hematopoietic system and has been implicated in the development of leukemia and other human cancers. Inhibition of Myb is therefore emerging as a potential therapeutic strategy for these diseases. However, because of a lack of suitable inhibitors, the feasibility of therapeutic approaches based on Myb inhibition has not been explored. We have identified the triterpenoid Celastrol as a potent low-molecular-weight inhibitor of the interaction of Myb with its cooperation partner p300. We demonstrate that Celastrol suppresses the proliferative potential of acute myeloid leukemia (AML) cells while not affecting normal hematopoietic progenitor cells. Furthermore, Celastrol prolongs the survival of mice in a model of an aggressive AML. Overall, our work demonstrates the therapeutic potential of a small molecule inhibitor of the Myb/p300 interaction for the treatment of AML and provides a starting point for the further development of Myb-inhibitory compounds for the treatment of leukemia and, possibly, other tumors driven by deregulated Myb.

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