biostudies-literatureThomas EMaryland Department of Health’s Cigarette Restitution Fund Program and the National Cancer Institute—Cancer Center Support GrantNational Cancer InstituteNCI NIH HHSNational Institutes of Health2699https://www.ebi.ac.uk/biostudies/studies/S-EPMC9454942biostudies-literatureUnknown11(17)Prostate cancer (PCa) relies in part on AR-signaling for disease development and progression. Earlier, we developed drug candidate galeterone, which advanced through phase 2-clinical trials in treating castration-resistant PCa (CRPC). Subsequently, we designed, synthesized, and evaluated next-generation galeterone-analogs including VNPP433-3β which is potently efficacious against pre-clinical models of PCa. This study describes the mechanism of action of VNPP433-3β that promotes degradation of full-length AR (fAR) and its splice variant AR-V7 besides depleting MNK1/2 in in vitro and in vivo CRPC models that stably overexpresses fAR. VNPP433-3β directly engages AR within the cell and promotes proteasomal degradation of fAR and its splice variant AR-V7 by enhancing the interaction of AR withCellsNovel AR/AR-V7 and Mnk1/2 Degrader, VNPP433-3β: Molecular Mechanisms of Action and Efficacy in AR-Overexpressing Castration Resistant Prostate Cancer In Vitro and In Vivo Models.PMC9454942P30 CA134274P30CA134274R01CA224696R01 CA224696Ambulos NPKane MANjar VCOHuang WZhang YThomas EPurushottamachar PThankan RSWeber DJfalseNovel AR/AR-V7 and Mnk1/2 Degrader, VNPP433-3β: Molecular Mechanisms of Action and Efficacy in AR-Overexpressing Castration Resistant Prostate Cancer In Vitro and In Vivo Models.Prostate cancer (PCa) relies in part on AR-signaling for disease development and progression. Earlier, we developed drug candidate galeterone, which advanced through phase 2-clinical trials in treating castration-resistant PCa (CRPC). Subsequently, we designed, synthesized, and evaluated next-generation galeterone-analogs including VNPP433-3β which is potently efficacious against pre-clinical models of PCa. This study describes the mechanism of action of VNPP433-3β that promotes degradation of full-length AR (fAR) and its splice variant AR-V7 besides depleting MNK1/2 in in vitro and in vivo CRPC models that stably overexpresses fAR. VNPP433-3β directly engages AR within the cell and promotes proteasomal degradation of fAR and its splice variant AR-V7 by enhancing the interaction of AR with2022-01-01T00:00:00Z2022 Aug2026-04-08T12:09:08.729Z2025-02-19T04:38:50.662ZS-EPMC94549423607811210.3390/cells11172699