Illendula, AnuradhaPulikkan, John A.Zong, HongliangGrembecka, JolantaXue, LitingSen, SiddharthaZhou, YunpengBoulton, AdamKuntimaddi, AravindaGao, YanRajewski, Roger A.Guzman, Monica L.Castilla, Lucio H.Bushweller, John H.2017-05-082017-05-082015-02-13Illendula, A., Pulikkan, J. A., Zong, H., Grembecka, J., Xue, L., Sen, S., … Bushweller, J. H. (2015). A small-molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC delays leukemia in mice. Science (New York, N.Y.), 347(6223), 779–784. http://doi.org/10.1126/science.aaa0314https://hdl.handle.net/1808/24000This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science on 2015 February 13; 347(6223): 779–784, DOI: 10.1126/science.aaa0314.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.Article10.1126/science.aaa0314PMC4423805openAccess