{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T05:04:18Z","timestamp":1789621458884,"version":"build-2803163510"},"reference-count":60,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007904","name":"Texas A&M University","doi-asserted-by":"crossref","award":["UG3CA290353"],"award-info":[{"award-number":["UG3CA290353"]}],"id":[{"id":"10.13039\/100007904","id-type":"DOI","asserted-by":"crossref"}]},{"award":["UG3CA290353"],"award-info":[{"award-number":["UG3CA290353"]}],"id":[{"id":"https:\/\/ror.org\/01f5ytq51","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000928","name":"Welch Foundation","doi-asserted-by":"crossref","award":["A-0015"],"award-info":[{"award-number":["A-0015"]}],"id":[{"id":"10.13039\/100000928","id-type":"DOI","asserted-by":"crossref"}]},{"award":["A-0015"],"award-info":[{"award-number":["A-0015"]}],"id":[{"id":"https:\/\/ror.org\/00np6vq88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: The progression of prostate cancer to castration-resistant prostate cancer (CRPC) is often driven by constitutively active androgen receptor splice variants, such as AR-V7, which evade conventional androgen-deprivation therapies. This study aimed to develop a high-throughput, mechanism-based screening platform to identify natural-product-derived AR-V7 inhibitors from the NCI Program for Natural Product Discovery (NPNPD) library. Methods: A subset of prefractionated NPNPD samples was screened using a CRISPR-edited 22Rv1 cell line expressing endogenous AR-V7 fused to a HiBiT luminescent tag, enabling quantification of AR-V7 levels. Fractions that reduced the HiBiT signal were further evaluated in 22Rv1 and C4-2B CRPC cells and counter-screened in non-malignant RWPE-1 cells. Compounds demonstrating at least 90% inhibition in CRPC cells with no more than 10% toxicity in RWPE-1 cells underwent dose\u2013response analysis, Western blotting, quantitative PCR, and subfractionation to isolate and characterize active constituents. Results: Of the 704 prefractionated samples, five fractions met stringent activity and selectivity criteria, with three consistently suppressing full-length androgen receptor (AR), AR-V7, and prostate-specific antigen (PSA). Primary screening results in HiBiT-22Rv1 cells were validated by secondary dose\u2013response and Western blot assays, and hits were further prioritized to ensure toxicity remained at or below 10% in RWPE-1 cells. HiBiT-guided screening of 66 subfractions identified seven that robustly downregulated AR signaling, with reduced AR-V7 levels correlating with decreased CRPC cell viability. Chemical characterization revealed two active butanolides, isolitsealiicolide C and isolinderanolide B, which reduced AR and AR-V7 protein and mRNA levels, decreased PSA, downregulated Bcl-2, and induced cleaved PARP, consistent with apoptotic cell death in AR-positive CRPC models. Conclusions: This integrated high-throughput workflow efficiently identifies AR-V7\u2013targeted natural products from complex libraries and highlights isolitsealiicolide C and isolinderanolide B as promising scaffolds for overcoming androgen receptor\u2013driven resistance in CRPC.<\/jats:p>","DOI":"10.3390\/pharmaceutics18091158","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T09:31:57Z","timestamp":1789464717000},"page":"1158","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Developing a Fluorescence-Based High-Throughput Screening Method for Natural Product Fractions to Identify Inhibitors of AR-V7 for Castration-Resistant Prostate Cancer"],"prefix":"10.3390","volume":"18","author":[{"given":"Neha","family":"Tyagi","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Texas A&M University, College Station, TX 77843, 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Group, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA"},{"name":"Department of Chemistry and Physics, Hood College, Frederick, MD 21701, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4657-6895","authenticated-orcid":false,"given":"Christopher C.","family":"Thornburg","sequence":"additional","affiliation":[{"name":"Natural Products Support Group, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6537-3997","authenticated-orcid":false,"given":"Tanja","family":"Grkovic","sequence":"additional","affiliation":[{"name":"Natural Products Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick, MD 21702, USA"},{"name":"Molecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0772-4856","authenticated-orcid":false,"given":"Barry R.","family":"O\u2019Keefe","sequence":"additional","affiliation":[{"name":"Natural Products Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick, MD 21702, USA"},{"name":"Molecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5767-2367","authenticated-orcid":false,"given":"James C.","family":"Sacchettini","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9902-7101","authenticated-orcid":false,"given":"Chendil","family":"Damodaran","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Texas A&M University, College Station, TX 77843, 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