{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T13:02:50Z","timestamp":1789995770115,"version":"4.0.1"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Prostate cancer remains a major cause of cancer-related mortality among men, while resistance to androgen deprivation therapy emphasizes the need for new therapeutic strategies. Molecular hybridization of pharmacologically relevant heterocycles offers a rational approach for developing novel anticancer agents.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Twenty oxadiazole\u2013pyrazole hybrids (VS-01\u2013VS-20) were designed, synthesized, and evaluated using molecular docking against the androgen receptor (PDB ID: 1Z95), followed by\n                      <jats:italic>in vitro<\/jats:italic>\n                      antiproliferative assessment against androgen-dependent LNCaP and androgen-independent PC-3 prostate cancer cells. The lead compound was further investigated for its effects on androgen receptor expression, intracellular reactive oxygen species (ROS), cell-cycle progression, and apoptosis using flow cytometry and fluorescence microscopy. ADMET properties were additionally predicted computationally.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      VS-04 demonstrated a favorable interaction profile within the androgen receptor ligand-binding pocket and exhibited potent antiproliferative activity, with IC\n                      <jats:sub>50<\/jats:sub>\n                      values of 394.95 \u00b1 3.03 nM against PC-3 and 464.85 \u00b1 4.29 nM against LNCaP cells. Docking\u2013activity correlation analysis revealed a moderate and significant association between docking affinity and PC-3 antiproliferative activity, whereas no significant correlation was observed for LNCaP cells. VS-04 treatment produced a concentration-dependent reduction in androgen receptor expression and increased intracellular ROS levels. Mechanistic studies further demonstrated pronounced S-phase accumulation and induction of apoptosis, with the total apoptotic population increasing from 7.45% in control cells to 47.83% following VS-04 treatment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The integrated computational and experimental evaluation identified VS-04 as a promising oxadiazole\u2013pyrazole lead with potent antiproliferative activity against prostate cancer cells. Its activity was associated with AR modulation, oxidative stress, cell-cycle perturbation, and apoptotic cell death, supporting further structural optimization and preclinical investigation of this scaffold for prostate cancer therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1953079","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T12:02:11Z","timestamp":1789992131000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Preclinical identification of an oxadiazole-pyrazole lead targeting prostate cancer through integrated mechanistic evaluation"],"prefix":"10.3389","volume":"16","author":[{"given":"Vanktesh","family":"Kumar","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University","place":["Phagwara, Punjab, 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