{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:15:34Z","timestamp":1785428134914,"version":"3.56.0"},"posted":{"date-parts":[[2026,4,30]]},"group-title":"Cancer Biology","reference-count":38,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["W81XWH2211010"],"award-info":[{"award-number":["W81XWH2211010"]}],"id":[{"id":"https:\/\/ror.org\/0447fe631","id-type":"ROR","asserted-by":"publisher"}]},{"award":["5R01CA269635-01"],"award-info":[{"award-number":["5R01CA269635-01"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Second generation antiandrogens, such as enzalutamide, are commonly prescribed to treat advanced prostate cancer. However, enzalutamide resistant prostate cancer (ERPC) invariably develops with more aggressive features. Management of ERPC is extremely difficult not only because available therapies cannot effectively eliminate ERPC cells but also due to enhanced growth and highly metastatic features in ERPC cells to invade distant organs. This problem is amplified by the lack of proper knowledge about suitable molecular targets in ERPC cells. Recently, we reported that Tribbles 2 (TRIB2), is overexpressed in ERPC cells and tumors and inhibition of TRIB2 kills ERPC cells via apoptosis. TRIB2 enhances cancer cell growth and invasion and confers resistance to enzalutamide, while inhibition of TRIB2 resensitizes the resistant cells. Interestingly, TRIB2 induces neuroendocrine (NE) features in ERPC cells and both the\n                  <jats:italic>de novo<\/jats:italic>\n                  and treatment-emergent NEPC cells consistently overexpress TRIB2. Though TRIB2 has emerged as a promising target, suitable inhibitors are not commercially available for clinical use. We used artificial intelligence (AI)-based molecular modeling to design a series of small chemical entities with potentially high specificity to bind with TRIB2. Extensive virtual screening and molecular editing yielded few highly selective and potent agents to inhibit TRIB2 and kill ERPC-NE\/NEPC cells. One such compound (HF-125) directly binds to destabilize and degrade TRIB2 proteins involving proteasomes and is effective both\n                  <jats:italic>in vitro<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  . Based on these findings, HF-125 emerges as a promising novel agent for development of a new therapeutic strategy for ERPC-NE\/NEPC types of aggressive prostate cancer.\n                <\/jats:p>","DOI":"10.64898\/2026.04.27.720588","type":"posted-content","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T20:55:11Z","timestamp":1777582511000},"source":"Crossref","is-referenced-by-count":0,"title":["HF-125, a first-in-class computer-modeled novel inhibitor of Tribbles 2, for therapy of enzalutamide resistant, neuroendocrine prostate cancer"],"prefix":"10.64898","author":[{"given":"Sougata Ghosh","family":"Chowdhury","sequence":"first","affiliation":[{"name":"Department of Urology, Henry Ford Health System, Detroit, MI 48202, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pritam","family":"Biswas","sequence":"additional","affiliation":[{"name":"Department of Urology, Henry Ford Health System, Detroit, MI 48202, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jitender","family":"Monga","sequence":"additional","affiliation":[{"name":"Department of Urology, Henry Ford Health System, Detroit, MI 48202, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Henry Ford Health System, Detroit, MI 48202, United States"},{"name":"Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Rogers","sequence":"additional","affiliation":[{"name":"Department of Urology, Henry Ford Health System, Detroit, MI 48202, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jagadananda","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Department of Urology, Henry Ford Health System, Detroit, MI 48202, United States"},{"name":"Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026050421301166000_2026.04.27.720588v1.1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21871"},{"key":"2026050421301166000_2026.04.27.720588v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2014.07.028"},{"key":"2026050421301166000_2026.04.27.720588v1.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1405095"},{"key":"2026050421301166000_2026.04.27.720588v1.4","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.64.9285"},{"key":"2026050421301166000_2026.04.27.720588v1.5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1207506"},{"key":"2026050421301166000_2026.04.27.720588v1.6","first-page":"2153","article-title":"Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomized, double-blind, phase 2 study","volume":"17","year":"2016","journal-title":"Lancet Oncology"},{"key":"2026050421301166000_2026.04.27.720588v1.7","doi-asserted-by":"publisher","DOI":"10.1177\/1756287214555336"},{"key":"2026050421301166000_2026.04.27.720588v1.8","first-page":"2153","article-title":"Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomized, double-blind, phase 2 study","volume":"17","year":"2016","journal-title":"Lancet Oncology"},{"key":"2026050421301166000_2026.04.27.720588v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2014.08.006"},{"key":"2026050421301166000_2026.04.27.720588v1.10","doi-asserted-by":"crossref","first-page":"7353","DOI":"10.2147\/OTT.S153764","article-title":"Enzalutamide-resistant castration-resistant prostate cancer: challenges and solutions","volume":"11","year":"2018","journal-title":"OncoTargets and Therapy"},{"key":"2026050421301166000_2026.04.27.720588v1.11","doi-asserted-by":"crossref","first-page":"6649","DOI":"10.1038\/s41598-020-62845-8","article-title":"Pharmacological and genetic targeting of 5-lipoxygenase interrupts c-Myc oncogenic signaling and kills enzalutamide resistant prostate cancer cells via apoptosis","volume":"10","year":"2020","journal-title":"Scientific Reports"},{"issue":"2","key":"2026050421301166000_2026.04.27.720588v1.12","doi-asserted-by":"crossref","first-page":"101556","DOI":"10.1016\/j.jbc.2021.101556","article-title":"Tribbles 2 pseudokinase confers enzalutamide resistance in prostate cancer by promoting lineage plasticity","volume":"298","year":"2022","journal-title":"J. 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