Targeting Hippo pathway by specific interruption of YAP-TEAD interaction using cyclic YAP-like peptides

Zheng Zhou, Taishan Hu, Zhiheng Xu, Zhaohu Lin, Zhisen Zhang, Teng Feng, Liangcheng Zhu, Yiping Rong, Hong Shen, John M Luk, Xiongwen Zhang, Ning Qin
FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology 2015, 29 (2): 724-32
Hippo signaling pathway is emerging as a novel target for anticancer therapy because it plays key roles in organ size control and tumorigenesis. As the downstream effectors, Yes-associated protein (YAP)-transcriptional enhancer activation domain family member (TEAD) association is essential for YAP-driven oncogenic activity, while TEAD is largely dispensable for normal tissue growth. We present the design of YAP-like peptides (17mer) to occupy the interface 3 on TEAD. Introducing cysteines at YAP sites 87 and 96 can induce disulfide formation, as confirmed by crystallography. The engineered peptide significantly improves the potency in disrupting YAP-TEAD interaction in vitro. To confirm that blocking YAP-TEAD complex formation by directly targeting on TEAD is a valid approach, we report a significant reduction in tumor growth rate in a hepatocellular carcinoma xenograft model after introducing the dominant-negative mutation (Y406H) of TEAD1 to abolish YAP-TEAD interaction. Our results suggest that targeting TEAD is a promising strategy against YAP-induced oncogenesis.

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