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    Novel 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

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    Author
    Thomas, Elizabeth
    Thankan, Retheesh S.
    Purushottamachar, Puranik
    Huang, Weiliang
    Kane, Maureen A.
    Zhang, Yuji
    Ambulos, Nicholas P.
    Weber, David J.
    Njar, Vincent C.O.
    Date
    2022-08-30
    Journal
    Cells
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi:10.3390/cells11172699
    Abstract
    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 with E3 ligases MDM2/CHIP but disrupting AR-HSP90 binding. Next, VNPP433-3β decreases phosphorylation of 4EBP1 and abates binding of eIF4E and eIF4G to 5' cap of mRNA by depleting MNK1/2 with consequent depletion of phosphorylated eIF4E. Finally, RNA-seq demonstrates modulation of multiple pathways that synergistically contribute to PCa inhibition. Therefore, VNPP433-3β exerts its antitumor effect by imposing 1) transcriptional regulation of AR and AR-responsive oncogenes 2) translational regulation by disrupting mRNA-5'cap-dependent translation initiation, 3) reducing AR half-life through enhanced proteasomal degradation in vitro and AR-overexpressing tumor xenografts in vivo.
    Data Availibility
    The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
    Sponsors
    National Cancer Institute
    Keyword
    androgen receptor
    AR/AR-V7 degrader
    castration-resistant prostate cancer
    lead next generation galeterone analog
    MNK1/2-eIF4E
    prostate cancer transcriptome
    VNPP433-3β
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/19814
    ae974a485f413a2113503eed53cd6c53
    10.3390/cells11172699
    Scopus Count
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