Rational Design of Novel Allosteric EYA2 Inhibitors as Potential Therapeutics for Multiple Brain Cancers

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Eyes Absent (EYA) proteins, particularly EYA2, partner with SIX proteins to drive cancer metastasis and recurrence.
• EYA2 functions as a transcriptional coactivator and a tyrosine phosphatase, influencing DNA repair and inhibiting anti-tumor activity.

Purpose of the Study:

• To develop novel EYA2 inhibitors to prevent cancer progression and promote cell death.
• To structurally optimize a known EYA2 inhibitor (9987) for improved efficacy and drug-like properties.

Main Methods:

• Utilized in silico modeling, biochemical assays, and cell-based assays for structural optimization.
• Screened a new series of compounds derived from the initial inhibitor 9987.

Main Results:

• Developed compounds with enhanced cellular activity and improved physiochemical properties suitable for targeting the central nervous system.
• Compound 2e demonstrated over 30-fold improvement in medulloblastoma cell line D458 compared to 9987.
• Compound 2e maintained potent and selective inhibition of EYA2 tyrosine phosphatase activity and favorable CNS drug properties.

Conclusions:

• Targeting EYA2 offers a viable strategy to inhibit cancer progression, especially given the difficulty in targeting SIX proteins.
• The optimized compound 2e represents a promising lead for developing therapeutics against EYA2-driven cancers, including brain tumors.