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Design and Biochemical Characterization of Peptidic Inhibitors of the Myb/p300 Interaction. | LitMetric
The Myb transcription factor is involved in the proliferation of hematopoietic cells, and deregulation of its expression can lead to cancers such as leukemia. Myb interacts with various proteins, including the histone acetyltransferases p300 and CBP. Myb binds to a small domain of p300, the KIX domain (p300), and inhibiting this interaction is a potential new drug discovery strategy in oncology. The available structures show that Myb binds to a very shallow pocket of the KIX domain, indicating that it might be challenging to identify inhibitors of this interaction. Here, we report the design of Myb-derived peptides which interact with p300. We show that by mutating only two Myb residues that bind in or near a hotspot at the surface of p300, it is possible to obtain single-digit nanomolar peptidic inhibitors of the Myb/p300 interaction that bind 400-fold tighter to p300 than wildtype Myb. These findings suggest that it might also be possible to design potent low molecular-weight compounds to disrupt the Myb/p300 interaction.
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