Structure–activity relationship studies of allosteric inhibitors of <scp>EYA2</scp> tyrosine phosphatase

Anantharajan, Jothi; Baburajendran, Nithya; Lin, Grace; Loh, Yong Yao; Xu, Weijun; Ahmad, Nur Huda Binte; Liu, Shuang; Jasson, Anna E; Kuan, John Wee Liang; Ng, Elizabeth Yihui; Yeo, Yee Khoon; Hung, Alvin W.; Joy, Joma; Hill, Jeffrey; Ford, Heide L.; Zhao, Rui; Keller, Thomas H.; Kang, CongBao

doi:10.1002/pro.4234

Cited by 7 publications

(1 citation statement)

References 30 publications

(63 reference statements)

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“…There remains a dire need for new therapeutic strategies to treat patients with metastatic TNBC. Thus, these findings suggest a possible future avenue for inhibiting EYA3 as a means to target both MYC and NF-kB signaling, thus inhibiting both primary and metastatic TNBC 27,[71][72][73][74][75][76][77][78] .…”

Section: Introductionmentioning

confidence: 99%

An EYA3/NF-κB/CCL2 signaling axis suppresses cytotoxic NK cells in the pre-metastatic niche to promote triple negative breast cancer metastasis

Rosenbaum,

Hughes,

Fields

et al. 2024

Preprint

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Patients with Triple Negative Breast Cancer (TNBC) exhibit high rates of metastases and poor prognoses. The Eyes absent (EYA) family of proteins are developmental transcriptional cofactors/phosphatases that are re-expressed and/or upregulated in numerous cancers. Herein, we demonstrate that EYA3 correlates with decreased survival in breast cancer, and that it strongly, and specifically, regulates metastasis via a novel mechanism that involves NF-κB signaling and an altered innate immune profile at the pre-metastatic niche (PMN). Remarkably, restoration of NF-κB signaling downstream of Eya3 knockdown (KD) restores metastasis without restoring primary tumor growth, isolating EYA3/NF-κB effects to the metastatic site. We show that secreted CCL2, regulated downstream of EYA3/NF-κB, specifically decreases cytotoxic NK cells in the PMN and that re-expression of Ccl2 in Eya3-KD cells is sufficient to rescue activation/levels of cytotoxic NK cells in vitro and at the PMN, where EYA3-mediated decreases in cytotoxic NK cells are required for metastatic outgrowth. Importantly, analysis of public breast cancer datasets uncovers a significant correlation of EYA3 with NF-κB/CCL2, underscoring the relevance of EYA3/NF-κB/CCL2 to human disease. Our findings suggest that inhibition of EYA3 could be a powerful means to re-activate the innate immune response at the PMN, inhibiting TNBC metastasis.

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Section: Introductionmentioning

confidence: 99%

An EYA3/NF-κB/CCL2 signaling axis suppresses cytotoxic NK cells in the pre-metastatic niche to promote triple negative breast cancer metastasis

Rosenbaum,

Hughes,

Fields

et al. 2024

Preprint

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

Gardner,

Rossi,

Armstrong

et al. 2024

ChemMedChem

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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.

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Structure–activity relationship studies of allosteric inhibitors of EYA2 tyrosine phosphatase

et al. 2021

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Human eyes absent (EYA) proteins possess Tyr phosphatase activity, which is critical for numerous cancer and metastasis promoting activities, making it an attractive target for cancer therapy. In this work, we demonstrate that the inhibitor-bound form of EYA2 does not favour binding to Mg 2+ , which is indispensable for the Tyr phosphatase activity. We further describe characterization and optimization of this class of allosteric inhibitors. A series of analogues were synthesized to improve potency of the inhibitors and to elucidate structure-activity relationships. Two co-crystal structures confirm the binding modes of this class of inhibitors. Our medicinal chemical, structural, biochemical, and biophysical studies provide insight into the molecular interactions of EYA2 with these allosteric inhibitors. The compounds derived from this study are useful for exploring the function of the Tyr phosphatase activity of EYA2 in normal and cancerous cells and serve as reference compounds for screening or developing allosteric phosphatase inhibitors. Finally, the co-crystal structures reported in this study will aid in structure-based drug discovery against EYA2.

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Structure–activity relationship studies of allosteric inhibitors of EYA2 tyrosine phosphatase

Cited by 7 publications

References 30 publications

An EYA3/NF-κB/CCL2 signaling axis suppresses cytotoxic NK cells in the pre-metastatic niche to promote triple negative breast cancer metastasis

An EYA3/NF-κB/CCL2 signaling axis suppresses cytotoxic NK cells in the pre-metastatic niche to promote triple negative breast cancer metastasis

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

Structure–activity relationship studies of allosteric inhibitors of EYA2 tyrosine phosphatase

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