title: Chemical biology. A small-molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC delays leukemia in mice.
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.
authors: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
authors: Anuradha
authors: A
authors: Illendula
authors: Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors: John A
authors: JA
authors: Pulikkan
authors: Department of Medicine, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors: Hongliang
authors: H
authors: Zong
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Jolanta
authors: J
authors: Grembecka
authors: Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors: Liting
authors: L
authors: Xue
authors: Department of Medicine, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors: Siddhartha
authors: S
authors: Sen
authors: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
authors: Yunpeng
authors: Y
authors: Zhou
authors: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
authors: Adam
authors: A
authors: Boulton
authors: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
authors: Aravinda
authors: A
authors: Kuntimaddi
authors: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
authors: Yan
authors: Y
authors: Gao
authors: Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66045, USA.
authors: Roger A
authors: RA
authors: Rajewski
authors: Department of Medicine, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors: Monica L
authors: ML
authors: Guzman
authors: Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA. jhb4v@virginia.edu Lucio.Castilla@umassmed.edu.
authors: Lucio H
authors: LH
authors: Castilla
authors: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA. jhb4v@virginia.edu Lucio.Castilla@umassmed.edu.
authors: John H
authors: JH
authors: Bushweller
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000737:chemistry / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D050676:Core Binding Factor Alpha 2 Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000378:metabolism; D060066:Protein Interaction Maps; D054852:Small Molecule Libraries / Q000737:chemistry
chemical_list: C000595793:2,2'-(5,5'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(pyridine-5,2-diyl))bis(6-(trifluoromethoxy)-1H-benzo(d)imidazole); D000970:Antineoplastic Agents; D001562:Benzimidazoles; C095514:CBFbeta-MYH11 fusion protein; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; C493728:RUNX1 protein, human; D054852:Small Molecule Libraries