RT Journal Article
SR Electronic
T1 Discovery of a new class of reversible TEA-domain transcription factor inhibitors with a novel binding mode
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.05.24.493232
DO 10.1101/2022.05.24.493232
A1 Lu Hu
A1 Yang Sun
A1 Shun Liu
A1 Hannah Erb
A1 Alka Singh
A1 Junhao Mao
A1 Xuelian Luo
A1 Xu Wu
YR 2022
UL http://biorxiv.org/content/early/2022/05/24/2022.05.24.493232.abstract
AB The TEA domain (TEAD) transcription factor forms a transcription co-activation complex with the key downstream effector of the Hippo pathway, YAP/TAZ. TEAD-YAP controls the expression of Hippo-responsive genes involved in cell proliferation, development, and tumorigenesis. Hyperactivation of TEAD-YAP activities is observed in many human cancers, and is associated with cancer cell proliferation, survival and immune evasion. Therefore, targeting the TEAD-YAP complex has emerged as an attractive therapeutic approach. We previously reported that the mammalian TEAD transcription factors (TEAD1-4) possess auto-palmitoylation activities and contain an evolutionarily conserved palmitate-binding pocket (PBP), which allows small molecule modulation. Since then, several reversible and irreversible inhibitors have been reported by binding to PBP. Here, we report a new class of TEAD inhibitors with a novel binding mode. Representative analog TM2 shows potent inhibition of TEAD auto-palmitoylation both in vitro and in cells. Surprisingly, the co-crystal structure of the human TEAD2 YAP-binding domain (YBD) in complex with TM2 reveals that TM2 adopts an unexpected binding mode by occupying not only the hydrophobic PBP, but also a new side binding pocket formed by hydrophilic residues. RNA-seq analysis shows that TM2 potently and specifically suppresses TEAD-YAP transcriptional activities. Consistently, TM2 exhibits strong anti-proliferation effects as a single agent or in combination with a MEK inhibitor in YAP-dependent cancer cells. These findings establish TM2 as a promising small molecule inhibitor against TEAD-YAP activities and provide new insights for designing novel TEAD inhibitors with enhanced selectivity and potency.Competing Interest StatementH. L and X. W. are inventors of a patent application covering TM2 and analogues as novel TEAD inhibitors. Dr. Xu Wu has a financial interest in Tasca Therapuetics, which is developing small molecule modulators of TEAD palmitoylation and transcription factors. Dr. Wu's interests were reviewed and are managed by Mass General Hospital, and Mass General Brigham in accordance with their conflict of interest policies.