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A small-molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC delays leukemia in mice

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Science  13 Feb 2015:
Vol. 347, Issue 6223, pp. 779-784
DOI: 10.1126/science.aaa0314

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Toward drugging the undruggable in cancer

Many human cancers are characterized by inappropriate activity of transcription factors. These proteins are attractive drug targets in principle, but normalizing their function requires drugs that modulate specific protein-protein interactions, a goal that has been challenging. In acute myeloid leukemia, a chromosomal translocation creates an aberrant form of the transcription factor CBF-beta, which outcompetes “normal” CBF-beta for binding to another transcription factor called RUNX1, thereby deregulating its activity. Illendula et al. identified and chemically optimized a small molecule that selectively disrupts the interaction between the aberrant CBF-beta and RUNX1 (see the Perspective by Koehler and Chen). This molecule restored normal gene expression patterns and delayed leukemia progression in mice. Thus, transcription factors may not be as undruggable as once thought.

Science, this issue p. 779; see also p. 713