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
Author
Thomas, ElizabethThankan, Retheesh S.
Purushottamachar, Puranik
Huang, Weiliang
Kane, Maureen A.
Zhang, Yuji
Ambulos, Nicholas P.
Weber, David J.
Njar, Vincent C.O.
Date
2022-08-30Journal
CellsType
Article
Metadata
Show full item recordAbstract
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 InstituteKeyword
androgen receptorAR/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/10713/19814ae974a485f413a2113503eed53cd6c53
10.3390/cells11172699