Chemical biology. A small-molecule inhibitor of the aberrant transcription factor CBFbeta-SMMHC delays leukemia in mice
Department of Molecular, Cell and Cancer Biology
Medical Subject Headings
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
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.
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Citation: Science. 2015 Feb 13;347(6223):779-84. doi: 10.1126/science.aaa0314. Link to article on publisher's site
Illendula, Anuradha; Pulikkan, John A.; Zong, Hongliang; Grembecka, Jolanta; Xue, Liting; Sen, Siddhartha; Zhou, Yunpeng; Boulton, Adam; Kuntimaddi, Aravinda; Gao, Yan; Rajewski, Roger A.; Guzman, Monica L.; Castilla, Lucio H.; and Bushweller, John H., "Chemical biology. A small-molecule inhibitor of the aberrant transcription factor CBFbeta-SMMHC delays leukemia in mice" (2015). Molecular, Cell and Cancer Biology Publications. 15.