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Published on: July 25, 2013
Rational Design of Novel Allosteric EYA2 Inhibitors as Potential Therapeutics for Multiple Brain Cancers
Lukas Gardner1, John Rossi2, Brock Armstrong3
1Department of Chemistry, University of Colorado Boulder, 215 UCB, Boulder, CO, 80309.
Abstract:
The Eyes Absent (EYA) family of developmental proteins, often in partnership with the sine oculis (SIX) homeobox proteins, promote cancer metastasis and recurrence in numerous tumor types. In addition to being a transcriptional coactivator, EYA2 is a Tyr phosphatase that dephosphorylates H2AX which leads to repair instead of apoptosis upon DNA damage and ERβ which inhibits the anti-tumor transcriptional activity of ERβ. The SIX members of the EYA-SIX complex are difficult to target, therefore, we targeted the EYA2 to promote cell death and prevent cancer progression. We conducted structural optimization of a previously discovered allosteric inhibitor of EYA2, 9987, using the combination of in silico modeling, biochemical and cell-based assays. A new series of compounds was developed with significantly improved cellular activity and physiochemical properties desirable for brain targets. Specifically, compound 2 e showed >30-fold improvement in the medulloblastoma cell line D458, relative to 9987, while maintaining potent and selective inhibitory activity against EYA2 Tyr phosphatase activity and a good multiparameter optimization score for central nervous system drugs.
Insights
Researchers developed new compounds targeting the Eyes Absent protein 2 (EYA2) to combat cancer metastasis. Compound 2e shows significant improvement in medulloblastoma cells, offering a promising therapeutic strategy for brain tumors.
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.
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