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

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

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. jhb4v@virginia.edu Lucio.Castilla@umassmed.edu.
  • 7 Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA. jhb4v@virginia.edu Lucio.Castilla@umassmed.edu.
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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