{"doi":"10.1101/2023.05.05.539612","title":"Probing the mechanism of Cbl-b inhibition by a small-molecule inhibitor","abstract":"ABSTRACT Cbl-b is a RING-type E3 ubiquitin ligase that is expressed in several immune cell lineages, where it negatively regulates the activity of immune cells. Cbl-b has specifically been identified as an attractive target for cancer immunotherapy due to its role in promoting an immunosuppressive tumor environment, and Nx-1607, is in phase I clinical trials for advanced solid tumor malignancies. Using a suite of biophysical and cellular assays, we confirmed potent binding of C7683 (an analogue of Nx-1607) to the full-length Cbl-b and its N-terminal fragment containing the TKBD-LHR-RING domains. To further elucidate its mechanism of inhibition, we determined the co-crystal structure of Cbl-b with C7683, revealing compound interaction with both the TKBD and LHR, but not the ring domain. Here, we provide structural insights into a novel mechanism of Cbl-b inhibition by a small-molecule inhibitor that locks the protein in an inactive conformation by acting as an intramolecular glue.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":394517,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9629,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":36768,"name":"Sumera Perveen","orcid":"0000-0002-8898-9540","position":1,"is_corresponding":false},{"id":1042350,"name":"Magdalena Szewezyk","orcid":null,"position":2,"is_corresponding":false},{"id":311048,"name":"Hong Zeng","orcid":"0000-0002-9811-0421","position":3,"is_corresponding":false},{"id":462754,"name":"Aiping Dong","orcid":null,"position":4,"is_corresponding":false},{"id":277394,"name":"Fengling Li","orcid":"0000-0002-7962-9033","position":5,"is_corresponding":false},{"id":36728,"name":"Pegah Ghiabi","orcid":null,"position":6,"is_corresponding":false},{"id":805418,"name":"Yanjun Li","orcid":"0000-0002-9512-5265","position":7,"is_corresponding":false},{"id":36715,"name":"Irene Chau","orcid":"0000-0002-2313-973X","position":8,"is_corresponding":false},{"id":84362,"name":"C.H. Arrowsmith","orcid":"0000-0002-4971-3250","position":9,"is_corresponding":false},{"id":277408,"name":"Dalia Baršytė-Lovejoy","orcid":"0000-0002-6560-9621","position":10,"is_corresponding":false},{"id":691154,"name":"Vijayaratnam Santhakumar","orcid":"0000-0002-7001-557X","position":11,"is_corresponding":false},{"id":277407,"name":"Masoud Vedadi","orcid":"0000-0002-0574-0169","position":12,"is_corresponding":false},{"id":277395,"name":"Levon Halabelian","orcid":"0000-0003-4361-3619","position":13,"is_corresponding":false},{"id":1025944,"name":"Serah Kimani","orcid":"0000-0002-6960-3833","position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":null,"created_at":"2026-07-19T01:19:14.590635Z","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":[]}