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

Abstract

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 KIX ), 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 KIX . We show that by mutating only two Myb residues that bind in or near a hotspot at the surface of p300 KIX , it is possible to obtain single-digit nanomolar peptidic inhibitors of the Myb/p300 KIX interaction that bind 400-fold tighter to p300 KIX than wildtype Myb. These findings suggest that it might also be possible to design potent low molecular-weight compounds to disrupt the Myb/p300 KIX interaction.

Transcription Factor MYB as Therapeutic Target: Current Developments

“…Moreover, in vitro studies demonstrated that the mimic induced effects similar to Celastrol in AML cells, while in vivo experiments showed the prolonged survival of mice engrafted with patient-derived AML cells, mirroring the effects observed with Celastrol [ 21 , 79 ]. Encouraged by these promising results, various laboratories are currently engaged in the development of additional MYB-p300 inhibitory compounds [ 80 , 81 , 82 , 83 ].…”

Recent advances on anticancer and antimicrobial activities of directly-fluorinated five-membered heterocycles and their benzo-fused systems

“…This compound showed potent Hsp90 inhibition and represented a good candidate for the treatment of proliferation diseases. 72…”

Rapid-kinetics degron benchmarking reveals off-target activities and mixed agonism-antagonism of MYB inhibitors

“…MYB is a critical transcriptional dependency of acute myeloid leukemia (AML) 11,18,28,29 , where it has been a longterm focus of therapeutic efforts [30][31][32][33][34][35][36][37] , making AML a relevant context for functional characterization of MYB inhibitors. We therefore began by engineering a chemical degron model of MYB in AML cells.…”