{"doi":"10.15212/amm-2022-0022","title":"MDM2-BCL-XL PROTACs enable degradation of BCL-XL and stabilization of p53","abstract":"Inhibition or degradation of the anti-apoptotic protein BCL-X L is a viable strategy for cancer treatment. Despite the recent development of PROTACs for degradation of BCL-X L , the choice of E3 ligase has been restricted to VHL and CRBN. Herein, we report the development of MDM2-BCL-X L PROTACs using MDM2 as an E3 ligase for degradation of BCL-X L . Three MDM2-BCL-X L PROTACs derived from the MDM2 inhibitor Nutlin-3, which also upregulates p53, and the BCL-2/BCL-X L inhibitor ABT-263 with different linker lengths were designed, synthesized and evaluated in vitro. BMM4 exhibited potent, selective degradation activity against BCL-X L , and stabilized the tumor suppressor p53 in U87, A549 and MV-4-11 cancer cell lines. Moreover, the combination of BMM4 and the BCL-2 inhibitor ABT-199 showed synergistic antiproliferative activity. These unique bifunctional PROTACs offer an alternative strategy for targeted protein degradation.","journal":"Acta Materia Medica","year":2022,"id":271092,"datarank":0.3958585994422889,"base_score":2.639057329615259,"endowment":2.639057329615259,"self_citation_contribution":0.3958585994422889,"citation_network_contribution":0.0,"self_endowment_contribution":0.3958585994422889,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"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":935911,"name":"Feng Gao","orcid":"0000-0001-9801-2285","position":1,"is_corresponding":false},{"id":458639,"name":"Jing Chen","orcid":"0000-0001-8863-2843","position":2,"is_corresponding":false},{"id":879373,"name":"Giri Gnawali","orcid":null,"position":3,"is_corresponding":false},{"id":228323,"name":"Wei Wang","orcid":"0000-0003-4377-5060","position":4,"is_corresponding":false},{"id":878940,"name":"Mengyang Chang","orcid":"0000-0001-9679-8616","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:27:35.206187Z","pmid":"36910255","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":[]}