{"doi":"10.1101/2025.01.31.635109","title":"Small Molecule Modulation of MHC-I Surface Expression: A Click Chemistry-Based Discovery Approach","abstract":"ABSTRACT Immunotherapy has emerged as a powerful strategy for combating cancer by harnessing the patient’s immune system to recognize and eliminate malignant cells. Major histocompatibility complex class I (MHC-I) plays a pivotal role by presenting neoantigens to CD8+ T cells, triggering T cell-mediated killing. However, cancer cells often evade detection by downregulating MHC-I surface expression, hindering the immune response. This resistance mechanism offers an opportunity to bolster MHC-I surface expression via therapeutic interventions. We conducted a comprehensive evaluation of previously purported small molecule MHC-I inducers and identified heat shock protein 90 (Hsp90) inhibitors as privileged enhancers. Using a core scaffold, we employed an in situ click chemistry-based derivatization strategy to generate 380 novel compounds. New agents showed high induction levels, with one triazole-based analog, CliMB-325 , also enhancing T cell activation and exhibiting lower toxicity. Altogether, we demonstrated the potential of click chemistry-based diversification for discovering small molecules to counter immune evasion.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":555985,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9501,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":942826,"name":"Joey J. Kelly","orcid":null,"position":1,"is_corresponding":false},{"id":415714,"name":"Mahendra D. Chordia","orcid":"0000-0001-9364-4697","position":2,"is_corresponding":false},{"id":1454794,"name":"Yue Dou","orcid":"0009-0003-5557-0852","position":3,"is_corresponding":false},{"id":246680,"name":"Tian Zhang","orcid":"0000-0001-9007-7965","position":4,"is_corresponding":false},{"id":371227,"name":"Marcos M. Pires","orcid":"0000-0002-5676-0725","position":5,"is_corresponding":false},{"id":1303779,"name":"Sarah E. Newkirk","orcid":null,"position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-19T02:55:03.976486Z","pmid":"39975032","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":[]}