A small-molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC delays leukemia in mice Academic Article uri icon

Overview

MeSH Major

  • Antineoplastic Agents
  • Benzimidazoles
  • Leukemia, Myeloid, Acute
  • Oncogene Proteins, Fusion

abstract

  • Acute myeloid leukemia (AML) is the most common form of adult leukemia. The transcription factor fusion CBFβ-SMMHC (core binding factor β and the smooth-muscle myosin heavy chain), expressed in AML with the chromosome inversion inv(16)(p13q22), outcompetes wild-type CBFβ for binding to the transcription factor RUNX1, deregulates RUNX1 activity in hematopoiesis, and induces AML. Current inv(16) AML treatment with nonselective cytotoxic chemotherapy results in a good initial response but limited long-term survival. Here, we report the development of a protein-protein interaction inhibitor, 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.

publication date

  • February 13, 2015

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4423805

Digital Object Identifier (DOI)

  • 10.1126/science.aaa0314

PubMed ID

  • 25678665

Additional Document Info

start page

  • 779

end page

  • 84

volume

  • 347

number

  • 6223