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Joy ST, Henley MJ, De Salle SN, et al. A Dual-Site Inhibitor of CBP/p300 KIX is a Selective and Effective Modulator of Myb. J Am Chem Soc. 2021;143(37):15056-15062doi: 10.1021/jacs.1c04432.
Joy, S. T., Henley, M. J., De Salle, S. N., Beyersdorf, M. S., Vock, I. W., Huldin, A. J. L., & Mapp, A. K. (2021). A Dual-Site Inhibitor of CBP/p300 KIX is a Selective and Effective Modulator of Myb. Journal of the American Chemical Society, 143(37), 15056-15062. https://doi.org/10.1021/jacs.1c04432
Joy, Stephen T, et al. "A Dual-Site Inhibitor of CBP/p300 KIX is a Selective and Effective Modulator of Myb." Journal of the American Chemical Society vol. 143,37 (2021): 15056-15062. doi: https://doi.org/10.1021/jacs.1c04432
Joy ST, Henley MJ, De Salle SN, Beyersdorf MS, Vock IW, Huldin AJL, Mapp AK. A Dual-Site Inhibitor of CBP/p300 KIX is a Selective and Effective Modulator of Myb. J Am Chem Soc. 2021 Sep 22;143(37):15056-15062. doi: 10.1021/jacs.1c04432. Epub 2021 Sep 07. PMID: 34491719.
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J Am Chem Soc. 2021 Sep 22;143(37):15056-15062. doi: 10.1021/jacs.1c04432. Epub 2021 Sep 07.

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

Journal of the American Chemical Society

Stephen T Joy, Matthew J Henley, Samantha N De Salle, Matthew S Beyersdorf, Isaac W Vock, Allison J L Huldin, Anna K Mapp

Affiliations

  1. Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.
  2. Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  3. Interdisciplinary Research Experiences for Undergraduates Program, University of Michigan, Ann Arbor, Michigan 48109, United States.
  4. Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.

PMID: 34491719 DOI: 10.1021/jacs.1c04432

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 5600-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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