Chemical biology. A small-molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC delays leukemia in mice

  • Science. 2015 Feb 13;347(6223):779-84. doi: 10.1126/science.aaa0314.
Anuradha Illendula  1 ,  John A Pulikkan  2 ,  Hongliang Zong  3 ,  Jolanta Grembecka  4 ,  Liting Xue  2 ,  Siddhartha Sen  3 ,  Yunpeng Zhou  1 ,  Adam Boulton  1 ,  Aravinda Kuntimaddi  1 ,  Yan Gao  1 ,  Roger A Rajewski  5 ,  Monica L Guzman  3 ,  Lucio H Castilla  6 ,  John H Bushweller  7
Affiliations
  • 1. Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
  • 2. Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • 3. Department of Medicine, Weill Medical College of Cornell University, New York, NY 10065, USA.
  • 4. Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 5. Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66045, USA.
  • 6. Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA. [email protected] [email protected].
  • 7. Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA. [email protected] [email protected].
PMID: 25678665 DOI: 10.1126/science.aaa0314
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.

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