Exploring Degradation of Intrinsically Disordered Protein Yes-Associated Protein Induced by Proteolysis TArgeting Chimeras,Journal of Medicinal Chemistry

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Exploring Degradation of Intrinsically Disordered Protein Yes-Associated Protein Induced by Proteolysis TArgeting Chimeras
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-27 , DOI: 10.1021/acs.jmedchem.4c00815
Chen Zhou ₁ , Chunbao Sun ₂ , Miao Huang _{3,

4} , Xin Tang _{3,

4,

5} , Liya Pi ₂ , Chenglong Li ₁

Affiliation

Yes-associated protein (YAP) is a key oncogene in the Hippo tumor suppression pathway, historically challenging to target due to its intrinsically disordered nature. Leveraging recent advances in high-throughput screening that identified several YAP binders, we employed proteolysis-targeting chimera technology to develop a series of YAP degraders. Utilizing NSC682769, a known YAP binder, linked with VHL ligand 2 or pomalidomide via diverse linkers, we synthesized degraders including YZ-6. This degrader not only recruits the E3 ligase VHL for the rapid and sustained degradation of YAP but also effectively inhibits its nuclear localization, curtailing YAP/TEAD-mediated transcription in cancer cell lines such as NCI-H226 and Huh7. This dual action significantly diminishes YAP’s oncogenic activity, contributing to the potent antiproliferative effects observed both in vitro and in a Huh7 xenograft mouse model. These results underscore the potential of PROTAC-mediated YAP degradation as a strategy for treating YAP-driven cancers.

中文翻译：

探索蛋白水解靶向嵌合体诱导的内在无序蛋白 Yes 相关蛋白的降解

Yes相关蛋白（YAP）是Hippo肿瘤抑制途径中的关键癌基因，由于其本质上无序，历来难以靶向。利用鉴定了几种 YAP 结合物的高通量筛选的最新进展，我们采用蛋白水解靶向嵌合体技术开发了一系列 YAP 降解剂。利用 NSC682769（一种已知的 YAP 结合剂），通过不同的接头与 VHL 配体 2 或泊马度胺连接，我们合成了包括YZ-6在内的降解剂。这种降解剂不仅招募 E3 连接酶 VHL 来快速、持续地降解 YAP，而且还能有效抑制其核定位，从而减少 NCI-H226 和 Huh7 等癌细胞系中 YAP/TEAD 介导的转录。这种双重作用显着降低了 YAP 的致癌活性，有助于在体外和 Huh7 异种移植小鼠模型中观察到有效的抗增殖作用。这些结果强调了 PROTAC 介导的 YAP 降解作为治疗 YAP 驱动的癌症的策略的潜力。

更新日期：2024-08-27

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