{"doi":"10.1039/d2md00095d","title":"Scaffold hopping from indoles to indazoles yields dual MCL-1/BCL-2 inhibitors from MCL-1 selective leads","abstract":"Overexpression of the anti-apoptotic BCL-2 proteins is associated with the development and progression of a range of cancers. Venetoclax, an FDA-approved BCL-2 inhibitor, is fast becoming the standard-of-care for acute myeloid leukemia and chronic lymphocytic leukemia. However, the median survival offered by venetoclax is only 18 months (as part of a combination therapy regimen), and one of the primary culprits for this is the concomitant upregulation of sister anti-apoptotic proteins, in particular MCL-1 (and BCL-xL), which provides an escape route that manifests as venetoclax resistance. Since inhibition of BCL-xL leads to thrombocytopenia, we believe that a dual MCL-1/BCL-2 inhibitor may provide an enhanced therapeutic effect relative to a selective BCL-2 inhibitor. Beginning with a carboxylic acid-containing literature compound that is a potent inhibitor of MCL-1 and a moderate inhibitor of BCL-2, we herein describe our efforts to develop dual inhibitors of MCL-1 and BCL-2 by scaffold hopping from an indole core to an indazole framework. Subsequently, further elaboration of our novel N2-substituted, indazole-3-carboxylic acid lead into a family of indazole-3-acylsulfonamides resulted in improved inhibition of both MCL-1 and BCL-2, possibly through occupation of the p4 pocket, with minimal or no inhibition of BCL-xL.","journal":"RSC Medicinal Chemistry","year":2022,"id":269308,"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":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.944,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":932467,"name":"Christopher C. Goodis","orcid":null,"position":1,"is_corresponding":false},{"id":932468,"name":"Nathan G. Bowen","orcid":null,"position":2,"is_corresponding":false},{"id":309318,"name":"Wenbo Yu","orcid":"0000-0001-6962-5314","position":3,"is_corresponding":false},{"id":932469,"name":"Gregory E.A. Vickers","orcid":null,"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":421309,"name":"Brandon Drennen","orcid":null,"position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T00:27:18.142851Z","pmid":"36092148","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":[]}