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

Stephen T Joy1, Madeleine J Henley1,2, Samantha N De Salle1,2

  • 1Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.

Journal of the American Chemical Society
|September 7, 2021
PubMed

Insights

Researchers developed MybLL-tide, a potent dual-site inhibitor targeting the Myb-CBP/p300 KIX interaction crucial in acute myeloid leukemia (AML) and other cancers.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • The interaction between the KIX motif of CBP/p300 and the transcriptional activator Myb is implicated in certain acute myeloid leukemias (AML) and other cancers.
  • The CBP/p300 KIX domain presents a challenging target for small-molecule inhibitors due to its multiple binding sites, structural similarities to other domains, numerous binding partners, and conformational flexibility.

Purpose of the Study:

  • To develop a highly specific and potent small-molecule inhibitor targeting the Myb-CBP/p300 KIX interaction.
  • To investigate the efficacy of the developed inhibitor in blocking Myb-driven gene expression in AML cells.

Main Methods:

  • Design and synthesis of a picomolar dual-site inhibitor, MybLL-tide.
  • Affinity and selectivity profiling of MybLL-tide against the CBP/p300 KIX domain and other coactivator domains.
  • Assessment of MybLL-tide's ability to inhibit Myb·KIX-dependent gene expression in AML cells within the proteomic context.

Main Results:

  • MybLL-tide demonstrated picomolar affinity for the CBP/p300 KIX domain, significantly higher than previously reported compounds.
  • The inhibitor exhibited exceptional selectivity, with a 5600-fold preference for the CBP/p300 KIX domain over other coactivator domains.
  • MybLL-tide effectively blocked CBP and p300 association with Myb in cells, leading to the inhibition of key Myb·KIX-dependent genes in AML cells.

Conclusions:

  • MybLL-tide is a highly effective and modifiable tool for selectively targeting the CBP/p300 KIX domain.
  • This inhibitor can be used to assess transcriptional effects in AML cells and potentially other cancers with aberrant Myb activity.
  • The dual-site inhibition strategy holds promise for targeting other challenging coactivator domains with multiple binding surfaces.

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