A Dual-Site Inhibitor of CBP/p300 KIX is a Selective and Effective Modulator of Myb
| Autor: | Isaac W Vock, Allison J L Huldin, Matthew S. Beyersdorf, Anna K. Mapp, Stephen T. Joy, Matthew J. Henley, Samantha N. De Salle |
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| Rok vydání: | 2021 |
| Předmět: |
Binding Sites
Chemistry Context (language use) General Chemistry CREB-Binding Protein Biochemistry Catalysis Transcriptional Activator Myb Cell biology Proto-Oncogene Proteins c-myb Colloid and Surface Chemistry Gene Expression Regulation Protein Domains Cbp p300 Cell Line Tumor Coactivator Proteome Humans MYB Amino Acid Sequence Binding site Peptides E1A-Associated p300 Protein Gene Protein Binding |
| Zdroj: | Journal of the American Chemical Society. 143:15056-15062 |
| ISSN: | 1520-5126 0002-7863 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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