Chemical biology. A small-molecule inhibitor of the aberrant transcription factor CBFbeta-SMMHC delays leukemia in mice
Illendula, Anuradha ; Pulikkan, John A. ; Zong, Hongliang ; Grembecka, Jolanta ; Xue, Liting ; Sen, Siddhartha ; Zhou, Yunpeng ; Boulton, Adam ; Kuntimaddi, Aravinda ; Gao, Yan ... show 4 more
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Abstract
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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Science. 2015 Feb 13;347(6223):779-84. doi: 10.1126/science.aaa0314. Link to article on publisher's site