Abstract
The Hippo signaling pathway, which is implicated in the regulation of organ size, has emerged as a potential target for the development of cancer therapeutics. YAP, TAZ (transcription co-activators) and TEAD (transcription factor) are the downstream transcriptional machinery and effectors of the pathway. Formation of the YAP/TAZ-TEAD complex leads to transcription of growth-promoting genes. Conversely, disrupting the interactions of the complex decreases cell proliferation. Herein, we screened a 1000-member fragment library using Thermal Shift Assay and identified a hit fragment. We confirmed its binding at the YAP/TAZ-TEAD interface by X-ray crystallography, and showed that it occupies the same hydrophobic pocket as a conserved phenylalanine of YAP/TAZ. This hit fragment serves as a scaffold for the development of compounds that have the potential to disrupt YAP/TAZ-TEAD interactions. Structure-activity relationship studies and computational modeling were also carried out to identify more potent compounds that may bind at this validated druggable binding site.
Highlights
The Hippo signaling pathway and its components mainly function to control cell number and maintain organ size from early development through to adulthood.[1,2] When this delicate control of organ size is dysregulated, cell proliferation goes unchecked and massive outgrowth of tissue occurs, leading to cancer development.[3]
We screened a total of 1000 fragments from the Maybridge Ro3 fragment library, to identify fragments that bind to TEAD and could possibly disrupt the interaction between YAP/TAZ and TEAD
Mouse TEAD4 was used as the target protein as it has a high amino acid sequence homology with human TEADs (% 90%)
Summary
The Hippo signaling pathway and its components mainly function to control cell number and maintain organ size from early development through to adulthood.[1,2] When this delicate control of organ size is dysregulated, cell proliferation goes unchecked and massive outgrowth of tissue occurs, leading to cancer development.[3] The Hippo pathway was first discovered in Drosophila melanogaster; more recently, mammalian homologs of the proteins in the Hippo pathway have been characterized. The downstream transcriptional machinery, which consists of YAP, TAZ (transcription co-activators) and TEAD (transcription factor), is the terminal effector of the pathway.
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