Targeting Hippo pathway by specific interruption of YAP-TEAD interaction using cyclic YAP-like peptides.
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.
*Discovery Technology, Medicinal Chemistry, and Discovery Oncology, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China joe.zhou.jz2@roche.com.
Zheng
Z
Zhou
*Discovery Technology, Medicinal Chemistry, and Discovery Oncology, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China.
Taishan
T
Hu
*Discovery Technology, Medicinal Chemistry, and Discovery Oncology, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China.
Zhiheng
Z
Xu
*Discovery Technology, Medicinal Chemistry, and Discovery Oncology, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China.
Zhaohu
Z
Lin
*Discovery Technology, Medicinal Chemistry, and Discovery Oncology, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China.
Zhisen
Z
Zhang
*Discovery Technology, Medicinal Chemistry, and Discovery Oncology, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China.
Teng
T
Feng
*Discovery Technology, Medicinal Chemistry, and Discovery Oncology, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China.
Liangcheng
L
Zhu
*Discovery Technology, Medicinal Chemistry, and Discovery Oncology, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China.
Yiping
Y
Rong
*Discovery Technology, Medicinal Chemistry, and Discovery Oncology, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China.
Hong
H
Shen
*Discovery Technology, Medicinal Chemistry, and Discovery Oncology, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China.
John M
JM
Luk
*Discovery Technology, Medicinal Chemistry, and Discovery Oncology, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China.
Xiongwen
X
Zhang
*Discovery Technology, Medicinal Chemistry, and Discovery Oncology, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China.
Ning
N
Qin
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004220:Disulfides; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D000090683:Hippo Signaling Pathway; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D010456:Peptides, Cyclic / Q000737:chemistry; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D020349:Surface Plasmon Resonance; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D004220:Disulfides; D009687:Nuclear Proteins; D010455:Peptides; D010456:Peptides, Cyclic; D010750:Phosphoproteins; D000091262:TEA Domain Transcription Factors; C057182:TEAD1 protein, human; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D005982:Glutathione Transferase; D017346:Protein Serine-Threonine Kinases; D003545:Cysteine
HCC xenograft; TEAD-YAP crystal structure; disulfide cyclization