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

UMMS Affiliation

Department of Molecular, Cell and Cancer Biology

Publication Date


Document Type



Animals; Antineoplastic Agents; Benzimidazoles; Cell Line, Tumor; Core Binding Factor Alpha 2 Subunit; Female; Humans; Leukemia, Myeloid, Acute; Mice; Mice, Inbred C57BL; Oncogene Proteins, Fusion; Protein Interaction Maps; Small Molecule Libraries


Cancer Biology


Acute myeloid leukemia (AML) is the most common form of adult leukemia. The transcription factor fusion CBFbeta-SMMHC (core binding factor beta and the smooth-muscle myosin heavy chain), expressed in AML with the chromosome inversion inv(16)(p13q22), outcompetes wild-type CBFbeta 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 CBFbeta-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 CBFbeta-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.

DOI of Published Version



Science. 2015 Feb 13;347(6223):779-84. doi: 10.1126/science.aaa0314. Link to article on publisher's site

Journal/Book/Conference Title

Science (New York, N.Y.) (2,2'-(5,5'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(pyridine-5,2-diyl))bis(6-(trif luoromethoxy)-1H-benzo(d)imidazole))

Related Resources

Link to Article in PubMed

PubMed ID