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bioRxiv · 10.1101/2021.04.28.441843

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

Joy, S. T.·Henley, M. J.·De Salle, S. N.·Beyersdorf, M. J.·Vock, I. W.·Huldin, A. J. L.·Mapp, A.
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Abstract

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

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Joy, S. T., Henley, M. J., De Salle, S. N., Beyersdorf, M. J., Vock, I. W., Huldin, A. J. L., Mapp, A.. 2021-04-28. A Dual-Site Inhibitor of CBP/p300 KIX is a Selective and Effective Modulator of Myb. https://doi.org/10.1101/2021.04.28.441843

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