新型雄激素受体/雄激素受体剪接变异体 7 及丝裂原活化蛋白激酶 1/2 降解剂 VNPP433-3β：在雄激素受体过表达的去势抵抗性前列腺癌体外和体内模型中的作用机制及疗效。

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.

机构信息

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.

出版信息

Cells. 2022 Aug 30;11(17):2699. doi: 10.3390/cells11172699.

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.

前列腺癌（PCa）的发生和发展在一定程度上依赖于 AR 信号通路。此前，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）的 2 期临床试验中取得了进展。随后，我们设计、合成并评估了包括 VNPP433-3β在内的下一代 galeterone 类似物，该类似物在 PCa 的临床前模型中具有强大的疗效。本研究描述了 VNPP433-3β 的作用机制，该机制除了耗竭 MNK1/2 外，还能促进全长 AR（fAR）及其剪接变体 AR-V7 的降解，在体外和体内稳定过表达 fAR 的 CRPC 模型中均有疗效。VNPP433-3β 在细胞内直接与 AR 结合，并通过增强 AR 与 E3 连接酶 MDM2/CHIP 的相互作用，破坏 AR-HSP90 结合，从而促进 fAR 和其剪接变体 AR-V7 的蛋白酶体降解。接下来，VNPP433-3β 通过耗竭 MNK1/2 降低 4EBP1 的磷酸化，并阻止 eIF4E 和 eIF4G 与 mRNA 5' 帽的结合，从而减少磷酸化 eIF4E 的结合。最后，RNA-seq 表明，多种途径的协同调节有助于抑制 PCa。因此，VNPP433-3β 通过以下方式发挥其抗肿瘤作用：1）对 AR 和 AR 反应性癌基因的转录调控；2）通过破坏 mRNA 5' 帽依赖性翻译起始来进行翻译调控；3）通过增强体外蛋白酶体降解和体内 AR 过表达肿瘤异种移植中的 AR 半衰期来降低 AR 半衰期。