新型 AR/AR-V7 和 Mnk1/2 降解剂，VNPP433-3β：AR 过表达去势抵抗性前列腺癌体外和体内模型中的作用和功效分子机制,Cells

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新型 AR/AR-V7 和 Mnk1/2 降解剂，VNPP433-3β：AR 过表达去势抵抗性前列腺癌体外和体内模型中的作用和功效分子机制
Cells ( IF 5.1 ) Pub Date : 2022-08-30 , DOI: 10.3390/cells11172699
Elizabeth Thomas _{1,

2} , Retheesh S Thankan _{1,

3,

4} , Puranik Purushottamachar _{1,

2} , Weiliang Huang ₅ , Maureen A Kane ₅ , Yuji Zhang _{6,

7} , Nicholas P Ambulos ₈ , David J Weber _{2,

9,

10} , Vincent C O Njar _{1,

2,

9}

Affiliation

Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA.
The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA.
Flavocure Biotech, 701 E. Pratt St, Ste 2033, Baltimore, MD 21202, USA.
Isoprene Pharmaceuticals, Inc., 801 W Baltimore Street, Suite 502J, Baltimore, MD 21201, USA.
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
Division of Biostatistics and Bioinformatics, University of Maryland, Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA.
Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Department of Microbiology and Immunology, University of Maryland, Marlene Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA.
Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA.
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

前列腺癌 (PCa) 部分依赖于 AR 信号传导来促进疾病的发生和进展。早些时候，我们开发了候选药物 Galeterone，该药物在治疗去势抵抗性前列腺癌 (CRPC) 方面已通过 2 期临床试验。随后，我们设计、合成并评估了下一代加莱特酮类似物，包括 VNPP433-3β，它对 PCa 临床前模型有效。这项研究描述了 VNPP433-3β 的作用机制，除了在稳定过表达 fAR 的体外和体内 CRPC 模型中耗尽 MNK1/2 之外，还促进全长 AR (fAR) 及其剪接变体 AR-V7 的降解。VNPP433-3β 直接与细胞内的 AR 结合，并通过增强 AR 与 E3 连接酶 MDM2/CHIP 的相互作用但破坏 AR-HSP90 结合，促进 fAR 及其剪接变体 AR-V7 的蛋白酶体降解。接下来，VNPP433-3β 通过耗尽 MNK1/2 来降低 4EBP1 的磷酸化，并减少 eIF4E 和 eIF4G 与 mRNA 5' 帽的结合，从而耗尽磷酸化的 eIF4E。最后，RNA-seq 证明了多种途径的调节，可协同促进 PCa 抑制。因此，VNPP433-3β通过以下方式发挥其抗肿瘤作用：1）AR和AR反应性癌基因的转录调节；2）通过破坏mRNA-5'帽依赖性翻译起始进行翻译调节；3）通过增强蛋白酶体降解来减少AR半衰期。体外和体内 AR 过表达肿瘤异种移植物。

"点击查看英文标题和摘要"

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-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.

更新日期：2022-08-30

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