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

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

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Chickens
  • Disease Models, Animal
  • E1A-Associated p300 Protein / metabolism*
  • Gene Expression Regulation, Leukemic / drug effects
  • HL-60 Cells
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / pathology
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy*
  • Myeloid Cells / drug effects
  • Myeloid Cells / pathology
  • Protein Binding / drug effects
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-myb / metabolism*
  • Small Molecule Libraries / pharmacology
  • Small Molecule Libraries / therapeutic use*
  • Triterpenes / pharmacology
  • Triterpenes / therapeutic use

Substances

  • Proto-Oncogene Proteins c-myb
  • Small Molecule Libraries
  • Triterpenes
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • tripterine