{"doi":"10.1002/cmdc.202000278","title":"Rationally Designed Polypharmacology: α‐Helix Mimetics as Dual Inhibitors of the Oncoproteins Mcl‐1 and HDM2","abstract":"Protein-protein interactions (PPIs), many of which are dominated by α-helical recognition domains, play key roles in many essential cellular processes, and the dysregulation of these interactions can cause detrimental effects. For instance, aberrant PPIs involving the Bcl-2 protein family can lead to several diseases including cancer, neurodegenerative diseases, and diabetes. Interactions between Bcl-2 pro-life proteins, such as Mcl-1, and pro-death proteins, such as Bim, regulate the intrinsic pathway of apoptosis. p53, a tumor-suppressor protein, also has a pivotal role in apoptosis and is negatively regulated by its E3 ubiquitin ligase HDM2. Both Mcl-1 and HDM2 are upregulated in numerous cancers, and, interestingly, there is crosstalk between both protein pathways. Recently, synergy has been observed between Mcl-1 and HDM2 inhibitors. Towards the development of new anticancer drugs, we herein describe a polypharmacology approach for the dual inhibition of Mcl-1 and HDM2 by employing three densely functionalized isoxazoles, pyrazoles, and thiazoles as mimetics of key α-helical domains of their partner proteins.","journal":"ChemMedChem","year":2020,"id":81214,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9557,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":421309,"name":"Brandon Drennen","orcid":null,"position":1,"is_corresponding":false},{"id":421310,"name":"Maryanna E. Lanning","orcid":null,"position":2,"is_corresponding":false},{"id":421311,"name":"Samuel Hughes","orcid":null,"position":3,"is_corresponding":false},{"id":420253,"name":"Rebecca Rothhaas","orcid":"0000-0002-5292-768X","position":4,"is_corresponding":false},{"id":421312,"name":"Paul T. Wilder","orcid":null,"position":5,"is_corresponding":false},{"id":309315,"name":"Alexander D. MacKerell","orcid":"0000-0001-8287-6804","position":6,"is_corresponding":false},{"id":420254,"name":"Steven Fletcher","orcid":"0000-0002-4429-8334","position":7,"is_corresponding":false},{"id":421308,"name":"Ivie L. Conlon","orcid":null,"position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-18T21:52:34.401799Z","pmid":"32583936","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":[]}