{"doi":"10.1101/2021.04.28.441843","title":"A Dual-Site Inhibitor of CBP/p300 KIX is a Selective and Effective Modulator of Myb","abstract":"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","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":220691,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.959,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":561549,"name":"Matthew J. Henley","orcid":"0000-0002-0709-6186","position":1,"is_corresponding":false},{"id":712221,"name":"Samantha N. De Salle","orcid":null,"position":2,"is_corresponding":false},{"id":820142,"name":"Matthew S. Beyersdorf","orcid":"0000-0002-9400-4234","position":3,"is_corresponding":false},{"id":820143,"name":"Isaac W. Vock","orcid":"0000-0002-7178-6886","position":4,"is_corresponding":false},{"id":820380,"name":"Allison J. L. Huldin","orcid":null,"position":5,"is_corresponding":false},{"id":292063,"name":"Anna K. Mapp","orcid":"0000-0003-0791-8327","position":6,"is_corresponding":false},{"id":820141,"name":"Stephen T. Joy","orcid":"0000-0002-6030-7835","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-18T23:53:46.965811Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}