Design, Synthesis, and Bioevaluation of Transcriptional Enhanced Assocciated Domain (TEAD) PROTAC Degraders

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-04-22 DOI:10.1021/acsmedchemlett.4c00029

Huajie Li, Zhiming Ge, Kexin Lin, Wei He, Qinyu Chu, Mingyue Zheng*, Sulin Zhang* and Tianfeng Xu*,

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Abstract

Dysregulation of the Hippo pathway has been observed in various cancers. The transcription factor TEAD, together with its coactivators YAP/TAZ, plays a crucial role in regulating the transcriptional output of the Hippo pathway. Recently, extensive research has focused on small molecule inhibitors targeting TEAD, but studies on TEAD degraders are comparatively rare. In this study, we designed and synthesized a series of TEAD PROTACs by connecting a pan-TEAD inhibitor with the CRBN ligand thalidomide. A representative compound, 27, exhibited potent antiproliferative activity against NF2-deficient NCI-H226 cells. It dose-dependently induced TEAD degradation dependent on CRBN and proteasome system and decreased key YAP target genes CYR61 and CTGF expressions in NCI-H226 cells. Further degradation selectivity studies revealed that 27 exhibited more potent activity against TEAD2 compared to those of the other three family members in Flag-TEADs transfected 293T cells. Therefore, 27 may serve as a valuable tool for advancing biological studies related to TEAD2.

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转录增强同位结构域 (TEAD) PROTAC 降解剂的设计、合成和生物评估

在多种癌症中都观察到 Hippo 通路失调的现象。转录因子 TEAD 及其辅助激活因子 YAP/TAZ 在调节 Hippo 通路的转录输出方面发挥着至关重要的作用。最近，针对 TEAD 的小分子抑制剂成为广泛研究的重点，但有关 TEAD 降解剂的研究却相对较少。在本研究中，我们通过将泛 TEAD 抑制剂与 CRBN 配体沙利度胺连接起来，设计并合成了一系列 TEAD PROTACs。具有代表性的化合物 27 对 NF2 缺陷的 NCI-H226 细胞具有强效的抗增殖活性。它依赖于 CRBN 和蛋白酶体系统，剂量依赖性地诱导 TEAD 降解，并降低了 NCI-H226 细胞中关键 YAP 靶基因 CYR61 和 CTGF 的表达。进一步的降解选择性研究显示，在转染了 Flag-TEADs 的 293T 细胞中，与其他三个家族成员相比，27 对 TEAD2 的降解活性更强。因此，27 可作为推进 TEAD2 相关生物学研究的重要工具。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.