Novel Allosteric Effectors Targeting Human Transcription Factor TEAD.

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• The Hippo pathway regulates cellular processes and its dysregulation, specifically Yes-associated protein (YAP) overexpression, is linked to solid tumors.
• YAP interacts with TEAD transcription factors, making the TEAD-YAP complex a target for cancer therapeutics.
• The palmitate-binding pocket of TEAD proteins is a key target for inhibitor development.

Purpose of the Study:

• To identify novel allosteric inhibitors of the TEAD-YAP interaction.
• To chemically modify existing inhibitors to enhance their efficacy.
• To investigate the impact of ligand binding on protein conformational dynamics.

Main Methods:

• Screening of a DNA-encoded library against the TEAD central pocket.
• Chemical modification of identified inhibitors, replacing methyl amide with chloromethyl ketone.
• Computational analysis including molecular dynamics, free energy perturbation, and Markov state model analysis.

Main Results:

• Six new allosteric inhibitors were identified against the TEAD central pocket.
• Modified ligands showed enhanced allosteric communication between TEAD4 and YAP1 domains.
• Specific residues (Phe229, Thr332, Ile374, Ile395) were identified as crucial for inhibitor binding.

Conclusions:

• Chemical modification of allosteric inhibitors can improve their interaction with the TEAD-YAP complex.
• Enhanced allosteric communication suggests a promising mechanism for therapeutic intervention in YAP-driven cancers.
• The identified residues provide critical insights for future drug design targeting the Hippo pathway.