Eyes absent homolog 3 (EYA3) (EYA3)

Eyes absent homolog 3 (EYA3) is a multifunctional protein that serves as both a transcriptional co-activator and a protein tyrosine phosphatase (PTP). The C-terminal Eya Domain (ED) contains a unique haloacid dehalogenase (HAD)-like phosphatase motif that specifically dephosphorylates Tyr-142 of histone H2AX, a critical switch that determines whether a cell undergoes DNA repair or apoptosis following genotoxic stress (PubMed: 19234442). In many cancers, including breast cancer, Ewing sarcoma, and gastric cancer, EYA3 is overexpressed and promotes tumor progression by enhancing cell survival, migration, and angiogenesis through the regulation of VEGFA (PMID: 22545090, 34795211). Beyond oncology, EYA3-mediated phosphatase activity is a key driver of vascular remodeling in pulmonary arterial hypertension (PAH), making it a promising disease-modifying target (PMID: 31511520). Small molecule inhibitors such as the repurposed uricosuric agents benzbromarone and benzarone have demonstrated the ability to block EYA3 phosphatase activity, leading to reduced tumor growth and reversal of vascular remodeling in preclinical models. However, the development of EYA3-targeted therapies is complicated by the known hepatotoxicity of these lead compounds and the structural similarity between EYA family members, which necessitates the discovery of more selective and safer inhibitors.

Other names

Eyes absent 3EYA transcriptional coactivator and phosphatase 3Protein phosphatase EYA3Eyes absent homolog 3 (Drosophila)

Inhibition of the C-terminal Eya Domain (ED) tyrosine phosphatase activity, which prevents the dephosphorylation of H2AX at Tyr-142, thereby promoting apoptosis over DNA repair in stressed cells, and suppresses VEGFA-mediated angiogenic signaling.