{"doi":"10.1210/clinem/dgaa699","title":"Targeting Corticotroph HDAC and PI3-Kinase in Cushing Disease","abstract":"CONTEXT: Cushing disease (CD) is a life-threatening disorder. Therapeutic goals include symptom relief, biochemical control, and tumor growth inhibition. Current medical therapies for CD by and large exert no action on tumor growth. OBJECTIVE: To identify drugs that inhibit corticotroph tumor adrenocorticotropic hormone (ACTH) secretion and growth. DESIGN: High throughput screen employing a novel \"gain of signal\" ACTH AlphaLISA assay. SETTING: Academic medical center. PATIENTS: Corticotroph tumor tissues from patients with CD. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Potent inhibitors of corticotroph tumor ACTH secretion and growth. RESULTS: From a kinase inhibitor library, we identified the dual PI3K/HDAC inhibitor CUDC-907 as a potent inhibitor of murine and human corticotroph tumor ACTH secretion (median effective concentration 1-5 nM), and cell proliferation (median inhibitory concentration 5 nM). In an in vivo murine corticotroph tumor xenograft model, orally administered CUDC-907 (300 mg/kg) reduced corticotroph tumor volume (TV [cm3], control 0.17 ± 0.05 vs CUDC-907 0.07 ± 0.02, P < .05) by 65% and suppressed plasma ACTH (ACTH [pg/mL] control 206 ± 27 vs CUDC-907 47 ± 7, P < .05) and corticosterone (corticosterone [ng/mL] control 180 ± 87 vs CUDC-907 27 ± 5, P < .05) levels by 77% and 85% respectively compared with controls. We also demonstrated that CUDC-907 acts through HDAC1/2 inhibition at the proopiomelanocortin transcriptional level combined with its PI3K-mediated inhibition of corticotroph cell viability to reduce ACTH secretion. CONCLUSIONS: Given its potent efficacy in in vitro and in vivo models of CD, combined with proven safety and tolerance in clinical trials, we propose CUDC-907 may be a promising therapy for CD.","journal":"The Journal of Clinical Endocrinology & Metabolism","year":2020,"id":101812,"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":27,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9606,"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":266371,"name":"Robert Damoiseaux","orcid":"0000-0002-7611-7534","position":1,"is_corresponding":false},{"id":498557,"name":"Lilit Babayan","orcid":null,"position":2,"is_corresponding":false},{"id":498558,"name":"Everett Kanediel Rivera-Meza","orcid":null,"position":3,"is_corresponding":false},{"id":241798,"name":"Yingying Yang","orcid":"0000-0001-6779-080X","position":4,"is_corresponding":false},{"id":498559,"name":"Marvin Bergsneider","orcid":null,"position":5,"is_corresponding":false},{"id":497849,"name":"Marilene B. Wang","orcid":"0000-0002-2799-6325","position":6,"is_corresponding":false},{"id":279706,"name":"William H. Yong","orcid":null,"position":7,"is_corresponding":false},{"id":497850,"name":"Kathleen A. Kelly","orcid":"0000-0002-0206-9402","position":8,"is_corresponding":false},{"id":241815,"name":"Anthony P. Heaney","orcid":"0000-0003-3865-0810","position":9,"is_corresponding":false},{"id":497848,"name":"Dongyun Zhang","orcid":"0000-0002-0751-7809","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-18T22:40:22.678835Z","pmid":"33000123","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":[]}