Small-Molecule Cyanamide Pan-TEAD·YAP1 Covalent Antagonists.

Area of Science:

• Molecular Biology
• Medicinal Chemistry
• Oncology

Background:

• Transcriptional Enhanced Associate Domains (TEADs) are transcription factors crucial for regulating genes involved in tissue homeostasis, organ size, and cancer progression.
• TEADs interact with coactivators like Yes-Associated Protein (YAP) and Transcriptional Coactivator with PDZ-binding motif (TAZ) to control gene expression.

Purpose of the Study:

• To develop novel small molecules that covalently inhibit TEAD transcription factors.
• To investigate the mechanism of action and structure-activity relationships of these inhibitors.
• To evaluate the efficacy of these compounds in inhibiting TEAD activity and impacting cancer cell viability.

Main Methods:

• Design and synthesis of isoindoline and octahydroisoindole small molecules with a cyanamide electrophile.
• Biochemical assays to determine inhibition constants (k_inact/K_I) and IC50 values for YAP1 binding inhibition.
• Cocrystallography to elucidate structure-activity relationships.
• Cell-based assays to measure CTGF mRNA levels, TEAD transcriptional activity, and cancer cell viability.

Main Results:

• Developed small molecules that form covalent bonds with a conserved cysteine in the TEAD palmitate-binding cavity.
• Achieved high second-order rate constants (k_inact/K_I > 100 M^-1 s^-1) and submicromolar IC50 values for YAP1 binding inhibition.
• Demonstrated suppression of CTGF mRNA and inhibition of TEAD transcriptional activity in mammalian cells.
• Showed significant inhibition of cell viability in sarcoma, hepatocellular carcinoma, glioblastoma, and breast cancer cell lines with single-digit micromolar IC50 values.

Conclusions:

• Novel covalent inhibitors of TEADs have been developed, targeting the palmitate-binding pocket.
• These compounds effectively inhibit TEAD-YAP/TAZ interactions and downstream transcriptional activity.
• The developed inhibitors demonstrate potent anti-cancer activity across multiple tumor types, suggesting therapeutic potential.