Design and Biochemical Characterization of Peptidic Inhibitors of the Myb/p300 Interaction

• DOI: 10.1021/acs.biochem.2c00690
• Publication Date: 2023-03-08T09:49:56Z
• Authors: Matthew Jones; Philipp Grosche; Andreas Floersheimer; Jérome André; Raphael Gattlen; Dieter Oser; Juliette Tinchant; Roman Wille; Barbara Chie-Leon; Marc Gerspacher; Peter Ertl; Nils Ostermann; Eva Altmann; Eusebio Manchado; Thomas Vorherr; Patrick Chène
• Keywords: MYB; P300-CBP Transcription Factors; Transcription

The Myb transcription factor is involved in the proliferation of hematopoietic cells, and deregulation its expression can lead to cancers such as leukemia. interacts with various proteins, including histone acetyltransferases p300 CBP. binds a small domain p300, KIX (p300KIX), inhibiting this interaction potential new drug discovery strategy oncology. available structures show that very shallow pocket domain, indicating it might be challenging identify inhibitors interaction. Here, we report design Myb-derived peptides which interact p300KIX. We by mutating only two residues bind or near hotspot at surface p300KIX, possible obtain single-digit nanomolar peptidic Myb/p300KIX 400-fold tighter p300KIX than wildtype Myb. These findings suggest also potent low molecular-weight compounds disrupt