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
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-genera...
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MDPI AG
2022-08-01
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| Online Access: | https://www.mdpi.com/2073-4409/11/17/2699 |
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| author | Elizabeth Thomas Retheesh S. Thankan Puranik Purushottamachar Weiliang Huang Maureen A. Kane Yuji Zhang Nicholas P. Ambulos David J. Weber Vincent C. O. Njar |
| author_facet | Elizabeth Thomas Retheesh S. Thankan Puranik Purushottamachar Weiliang Huang Maureen A. Kane Yuji Zhang Nicholas P. Ambulos David J. Weber Vincent C. O. Njar |
| author_sort | Elizabeth Thomas |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T01:57:23Z |
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| last_indexed | 2024-03-10T01:57:23Z |
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| series | Cells |
| spelling | doaj.art-ed4a9e55a96344d8be6eace22976fdc52023-11-23T12:55:33ZengMDPI AGCells2073-44092022-08-011117269910.3390/cells11172699Novel 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 ModelsElizabeth Thomas0Retheesh S. Thankan1Puranik Purushottamachar2Weiliang Huang3Maureen A. Kane4Yuji Zhang5Nicholas P. Ambulos6David J. Weber7Vincent C. O. Njar8Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USADepartment of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USADepartment of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USADepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USADepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USADivision of Biostatistics and Bioinformatics, University of Maryland, Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USADepartment of Microbiology and Immunology, University of Maryland, Marlene Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USAThe Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USADepartment of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USAProstate 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.https://www.mdpi.com/2073-4409/11/17/2699castration-resistant prostate cancerprostate cancer transcriptomelead next generation galeterone analogVNPP433-3βandrogen receptorAR/AR-V7 degrader |
| spellingShingle | Elizabeth Thomas Retheesh S. Thankan Puranik Purushottamachar Weiliang Huang Maureen A. Kane Yuji Zhang Nicholas P. Ambulos David J. Weber Vincent C. O. Njar 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 Cells castration-resistant prostate cancer prostate cancer transcriptome lead next generation galeterone analog VNPP433-3β androgen receptor AR/AR-V7 degrader |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | castration-resistant prostate cancer prostate cancer transcriptome lead next generation galeterone analog VNPP433-3β androgen receptor AR/AR-V7 degrader |
| url | https://www.mdpi.com/2073-4409/11/17/2699 |
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