Journal Article

Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling

Song, Kijun, Gray, Nathanael S, Ji, Wenzhi, Lakhani, Jimit, Mancias, Joseph D, Che, Jianwei, He, Zhixiang, Tse, Jason, Boghossian, Andrew S, Roth, Jennifer A, Zhang, Tinghu, Rees, Matthew G, Ronan, Melissa M, Lu, Wenchao, Fan, Mengyang, Gao, Yang, Geffken, Ezekiel A, Seo, Hyuk-Soo, Gokhale, Prafulla C, Liu, Yao, Marto, Jarrod A, Ficarro, Scott B, Kwiatkowski, Nicholas P, Jiang, Jie, Kuljanin, Miljan, Dhe-Paganon, Sirano

2022

Overview

The transcription factor TEAD, together with its coactivator YAP/TAZ, is a key transcriptional modulator of the Hippo pathway. Activation of TEAD transcription by YAP has been implicated in a number of malignancies, and this complex represents a promising target for drug discovery. However, both YAP and its extensive binding interfaces to TEAD have been difficult to address using small molecules, mainly due to a lack of druggable pockets. TEAD is post-translationally modified by palmitoylation that targets a conserved cysteine at a central pocket, which provides an opportunity to develop cysteine-directed covalent small molecules for TEAD inhibition. Here, we employed covalent fragment screening approach followed by structure-based design to develop an irreversible TEAD inhibitor MYF-03–69. Using a range of in vitro and cell-based assays we demonstrated that through a covalent binding with TEAD palmitate pocket, MYF-03–69 disrupts YAP-TEAD association, suppresses TEAD transcriptional activity and inhibits cell growth of Hippo signaling defective malignant pleural mesothelioma (MPM). Further, a cell viability screening with a panel of 903 cancer cell lines indicated a high correlation between TEAD-YAP dependency and the sensitivity to MYF-03–69. Transcription profiling identified the upregulation of proapoptotic BMF gene in cancer cells that are sensitive to TEAD inhibition. Further optimization of MYF-03–69 led to an in vivo compatible compound MYF-03–176, which shows strong antitumor efficacy in MPM mouse xenograft model via oral administration. Taken together, we disclosed a story of the development of covalent TEAD inhibitors and its high therapeutic potential for clinic treatment for the cancers that are driven by TEAD-YAP alteration.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Animals / Antitumor activity / Apoptosis / Biochemistry and Chemical Biology / Cell viability / covalent ligand / Cysteine / Gene expression / Hippo Signaling Pathway / Humans / Interfaces / Kinases / Libraries / Lung cancer / Malignancy / Mass spectrometry / Medical prognosis / Mesothelioma / Mice / Optimization / Oral administration / Palmitic acid / Palmitoylation / Peptides / Post-translation / Proteins / Research Design / Scientific imaging / TEAD / Transcription activation / transcription factors / Transcriptional Activation / Transplantation, Heterologous / Tumor cell lines / Tumorigenesis / Xenografts / YAP / Yes-associated protein