{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T13:42:47Z","timestamp":1768743767208,"version":"3.49.0"},"reference-count":55,"publisher":"The Endocrine Society","issue":"1","license":[{"start":{"date-parts":[[2020,9,28]],"date-time":"2020-09-28T00:00:00Z","timestamp":1601251200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Multi-campus Research Programs","award":["MRP-17-454909"],"award-info":[{"award-number":["MRP-17-454909"]}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>To identify drugs that inhibit corticotroph tumor adrenocorticotropic hormone (ACTH) secretion and growth.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Design<\/jats:title>\n                  <jats:p>High throughput screen employing a novel \u201cgain of signal\u201d ACTH AlphaLISA assay.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Setting<\/jats:title>\n                  <jats:p>Academic medical center.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Patients<\/jats:title>\n                  <jats:p>Corticotroph tumor tissues from patients with CD.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Interventions<\/jats:title>\n                  <jats:p>None.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Main outcome measures<\/jats:title>\n                  <jats:p>Potent inhibitors of corticotroph tumor ACTH secretion and growth.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>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 \u00b1 0.05 vs CUDC-907 0.07 \u00b1 0.02, P &amp;lt; .05) by 65% and suppressed plasma ACTH (ACTH [pg\/mL] control 206 \u00b1 27 vs CUDC-907 47 \u00b1 7, P &amp;lt; .05) and corticosterone (corticosterone [ng\/mL] control 180 \u00b1 87 vs CUDC-907 27 \u00b1 5, P &amp;lt; .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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgaa699","type":"journal-article","created":{"date-parts":[[2020,10,30]],"date-time":"2020-10-30T06:00:59Z","timestamp":1604037659000},"page":"e232-e246","source":"Crossref","is-referenced-by-count":23,"title":["Targeting Corticotroph HDAC and PI3-Kinase in Cushing 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