2. Academic Validation
  3. Rational design of novel allosteric EYA2 inhibitors as potential therapeutics for multiple brain cancers

Rational design of novel allosteric EYA2 inhibitors as potential therapeutics for multiple brain cancers

  • ChemMedChem. 2024 Jun 11:e202400179. doi: 10.1002/cmdc.202400179.
Lukas Gardner 1,  John Rossi 2,  Brock Armstrong 3,  Mia Muse 4,  Alex LaVeck 1,  Melanie Blevins 5,  Lingdi Zhang 5,  Heide Ford 3,  Rui Zhao 2,  Xiang Wang 6
Affiliations

Affiliations

  • 1 CU Boulder, Chemistry, Cristol Chemistry, 215 UCB, 80309, Boulder, UNITED STATES.
  • 2 CU Anschutz School of Medicine, Biochemistry and Molecular Genetics, 12801 East 17th Ave, Mailstop 8101, 80045, Aurora, UNITED STATES.
  • 3 CU Anschutz School of Medicine, Pharmacology, 12800 East 19th Ave, Mailstop 6126, 80045, Aurora, UNITED STATES.
  • 4 CU Boulder, Chemistry, 215 UCB, Cristol Chemistry, 80309, Boulder, UNITED STATES.
  • 5 UNIVERSITY OF COLORADO, Department of Biochemistry and Molecular Genetics, 12801 East 17th Avenue, Mailstop 8101, 80045, Aurora, UNITED STATES OF AMERICA.
  • 6 University of Colorado Boulder, Department of Chemistry and Biochemistry, UCB 215, 80309, Boulder, UNITED STATES OF AMERICA.
PMID: 38861151 DOI: 10.1002/cmdc.202400179
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 2e 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.

Keywords

Allosteric Inhibitor; Central Nervous System; EYA2; Medulloblastoma; glioblastoma.

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