A Dual-Site Inhibitor of CBP/p300 KIX is a Selective and Effective Modulator of Myb

• Published in: bioRxiv
• Main Authors: Joy, Stephen T, Henley, Matthew J, De Salle, Samantha N, Beyersdorf, Matthew J, Vock, Isaac W, Allison Jl Huldin, Mapp, Anna
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 28.04.2021
• Subjects: Binding sites; Protein interaction; Proteomes; Transcription
• DOI: 10.1101/2021.04.28.441843

The protein-protein interaction between the KIX motif of the transcriptional coactivator CBP/p300 and the transcriptional activator Myb is a high value target due to its established role in certain acute myeloid leukemias (AML) and potential contributions to other cancers. However, the CBP/p300 KIX domain has multiple binding sites, several structural homologues, many binding partners, and substantial conformational plasticity, making it challenging to specifically target using small molecule inhibitors. Here, we report a picomolar dual-site inhibitor (MybLL-tide) of the Myb-CBP/p300 KIX interaction. MybLL-tide has higher affinity for CBP/p300 KIX than any previously reported compounds while also possessing 16,000-fold selectivity for the CBP/p300 KIX domain over other coactivator domains. MybLL-tide blocks the association of CBP and p300 with Myb in the context of the proteome leading to inhibition of key Myb-KIX-dependent genes in AML cells. These results show that MybLL-tide is an effective, modifiable tool to selectively target the KIX domain and assess transcriptional effects in AML cells and potentially other cancers featuring aberrant Myb behavior. Additionally, the dual-site design has applicability to the other challenging coactivators that bear multiple binding surfaces. Competing Interest Statement The authors have declared no competing interest.