Lu Yuhang, Yan Ziqin, Sun Jiaqi, Wang Chenxu, Xu Lan, Lyu Xilin, Wang Xiancheng, Lou Jianfeng, Huang He, Meng Linghua, Zhao Yujun
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China.
University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
J Med Chem. 2025 Mar 13;68(5):5616-5640. doi: 10.1021/acs.jmedchem.4c02884. Epub 2025 Jan 13.
Genetic mutations in components of the Hippo pathway frequently lead to the aberrant activation of TEADs, which is often associated with cancer. Consequently, TEADs have been actively pursued as therapeutic targets for diseases driven by TEAD overactivation. In this study, we report two series of TEAD PROTACs based on CRBN binders and VHL binders. Both series yielded potent TEAD degraders, including and (H122), which induced TEAD1 degradation with DC < 10 nM. Mechanistic studies demonstrated that the degradation of TEAD1 induced by relied on CRBN binding, TEAD1 binding, E3 ligase activity, and a functional proteasome. RNA-seq analyses indicated that significantly downregulated the expression of Myc target genes, as highlighted by GSEA analysis. More importantly, exhibited robust antitumor efficacy in the MSTO-211H mouse xenograft model. Collectively, our results suggest that TEAD PROTACs have therapeutic potential for the treatment of cancers associated with TEAD overactivation.
Hippo信号通路成分中的基因突变常常导致TEADs的异常激活，这通常与癌症相关。因此，TEADs一直被积极地作为由TEAD过度激活驱动的疾病的治疗靶点来研究。在本研究中，我们报道了基于CRBN结合剂和VHL结合剂的两个系列的TEAD PROTACs。两个系列都产生了强效的TEAD降解剂，包括 和 （H122），它们以DC < 10 nM诱导TEAD1降解。机制研究表明， 诱导的TEAD1降解依赖于CRBN结合、TEAD1结合、E3连接酶活性和功能性蛋白酶体。RNA测序分析表明， 显著下调了Myc靶基因的表达，基因集富集分析突出了这一点。更重要的是， 在MSTO-211H小鼠异种移植模型中表现出强大的抗肿瘤功效。总体而言，我们的结果表明，TEAD PROTACs对于治疗与TEAD过度激活相关的癌症具有治疗潜力。
