De Novo Design of an Androgen Receptor DNA Binding Domain-Targeted peptide PROTAC for Prostate Cancer Therapy,Advanced Science

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De Novo Design of an Androgen Receptor DNA Binding Domain-Targeted peptide PROTAC for Prostate Cancer Therapy
Advanced Science ( IF 14.3 ) Pub Date : 2022-08-15 , DOI: 10.1002/advs.202201859
Bohan Ma ₁ , Yizeng Fan ₁ , Dize Zhang ₁ , Yi Wei ₁ , Yanlin Jian ₁ , Donghua Liu ₁ , Zixi Wang ₁ , Yang Gao ₁ , Jian Ma ₁ , Yule Chen ₁ , Shan Xu ₁ , Lei Li ₁

Affiliation

Androgen receptor splice variant-7 (AR-V7), one of the major driving factors, is the most attractive drug target in castration-resistant prostate cancer (CRPC). Currently, no available drugs efficiently target AR-V7 in clinical practice. The DNA binding domain (DBD) is indispensable for the transcriptional activity of AR full length and AR splice variants, including AR-V7. Based on the homodimerization structure of the AR DBD, a novel peptide-based proteolysis-targeting chimera (PROTAC) drug is designed to induce AR and AR-V7 degradation in a DBD and MDM2-dependent manner, without showing any activity on other hormone receptors. To overcome the short half-life and poor cell penetrability of peptide PROTAC drugs, an ultrasmall gold (Au)-peptide complex platform to deliver the AR DBD PROTAC in vivo is developed. The obtained Au-AR pep-PROTAC effectively degrades AR and AR-V7 in prostate cancer cell lines, particularly in CWR22Rv1 cells with DC₅₀ values 48.8 and 79.2 nM, respectively. Au-AR pep-PROTAC results in suppression of AR levels and induces tumor regression in both enzalutamide sensitive and resistant prostate cancer animal models. Further optimization of the Au-AR pep-PROTAC can ultimately lead to a new therapy for AR-V7-positive CRPC.

中文翻译：

用于前列腺癌治疗的雄激素受体 DNA 结合域靶向肽 PROTAC 的从头设计

雄激素受体剪接变体 7 (AR-V7) 是主要驱动因素之一，也是去势抵抗性前列腺癌 (CRPC) 中最有吸引力的药物靶点。目前，临床实践中尚无有效靶向 AR-V7 的药物。 DNA 结合域 (DBD) 对于 AR 全长和 AR 剪接变体（包括 AR-V7）的转录活性是不可或缺的。基于 AR DBD 的同二聚化结构，一种新型的基于肽的蛋白水解靶向嵌合体 (PROTAC) 药物被设计为以 DBD 和 MDM2 依赖性方式诱导 AR 和 AR-V7 降解，而不对其他激素受体表现出任何活性。为了克服肽 PROTAC 药物半衰期短和细胞渗透性差的问题，开发了一种超小型金 (Au)-肽复合物平台，可在体内递送 AR DBD PROTAC。获得的 Au-AR pep-PROTAC 有效降解前列腺癌细胞系中的 AR 和 AR-V7，特别是在 CWR22Rv1 细胞中，DC ₅₀值分别为 48.8 和 79.2 nM。 Au-AR pep-PROTAC 可抑制恩杂鲁胺敏感性和耐药性前列腺癌动物模型中的 AR 水平并诱导肿瘤消退。 Au-AR pep-PROTAC 的进一步优化最终可以带来 AR-V7 阳性 CRPC 的新疗法。

更新日期：2022-08-15

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