A Fragment Screen Identifies Acrylamide Covalent Inhibitors of the TEAD•YAP Protein-Protein Interaction
Biorxiv : the Preprint Server for Biology
|March 27, 2026
Summary
Researchers identified small molecules that inhibit the TEAD•YAP interaction by targeting a unique cysteine in the TEAD protein's palmitate pocket, offering a new therapeutic strategy for the Hippo pathway.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- The Hippo pathway regulates organ size and is crucial in development and cancer.
- TEA domain (TEAD) proteins interact with Yes-associated protein (YAP) to control target gene expression.
- The TEAD•YAP protein-protein interaction is a key target but considered undruggable.
Purpose of the Study:
- To identify small molecules that can allosterically inhibit the TEAD•YAP interaction.
- To explore the druggability of the TEAD protein's unique palmitate pocket.
Main Methods:
- Screening of an acrylamide electrophile fragment library against TEAD proteins.
- Synthesis and characterization of derived small-molecule inhibitors.
- Biochemical assays to determine reaction rates and binding constants.
- Co-crystal structure analysis of fragment-bound TEAD proteins.
Main Results:
- A fragment was identified that covalently binds to a conserved cysteine in the TEAD palmitate pocket, inhibiting TEAD•YAP binding.
- Structure determination revealed binding at the conserved cysteine and an additional cysteine in TEAD2.
- Kinetic and binding studies quantified the inhibitory potential of synthesized derivatives.
Conclusions:
- The TEAD palmitate pocket is a druggable target for developing allosteric inhibitors.
- Acrylamide-based covalent inhibitors targeting TEAD cysteine residues show promise for modulating the Hippo pathway.
- These findings represent a novel starting point for small-molecule drug development against TEAD•YAP interactions.
Related Concept Videos
01:30Enzyme Inhibition
94.9K
Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.
94.9K
01:19Allosteric Proteins-ATCase
6.9K
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
6.9K
02:04Covalently Linked Protein Regulators
9.9K
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
These groups modify specific amino acids in a protein....
9.9K
02:04Protein-protein Interfaces
15.0K
Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a...
15.0K
01:25Inhibitors of Bacterial Protein Synthesis
31
Aminoglycosides constitute a highly potent class of bactericidal antibiotics that exert their antimicrobial effects by targeting the bacterial ribosome, specifically disrupting protein synthesis. These polycationic molecules consist of amino-modified sugars linked via glycosidic bonds to an aminocyclitol core such as 2-deoxystreptamine or streptamine. Their strong positive charges facilitate tight binding to the negatively charged phosphate backbone of ribosomal RNA (rRNA), primarily at the 16S...
31