Identification and Screening of Selective WEE2 Inhibitors to Develop Non-Hormonal Contraceptives that Specifically Target Meiosis

Carol B. Hanna, Shan Yao, Mat Martin, Ernst Schönbrunn, Gunda I. Georg, Jeffrey T. Jensen, Rebecca A.D. Cuellar

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

We used a progressive elimination strategy to identify oocyte-specific WEE2 kinase inhibitors for potential non-hormonal contraceptives that target meiosis. Beginning with an in-house library of over 300,000 compounds, virtual high throughput screening identified 57 WEE2 inhibitors with preferential predicted binding over the somatic variant WEE1. Seven compounds were further evaluated in vitro by enzyme-linked immunosorbent assay to measure biochemical inhibition on WEE1 and WEE2 phosphorylation of CDK1. To assess specificity, we evaluated WEE2-mediated inhibition of meiosis using in vitro oocyte fertilization, and WEE1-mediated inhibition of mitosis using a somatic cell proliferation assay. Our results from these assays identified three candidates for further development: 6-(2,6-dichlorophenyl)-2-((4-(2-(diethylamino)ethoxy) phenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (2), 6-(2,6-dichlorophenyl)-8-methyl-2-((4-morpholinophenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (12), and 3-((6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)benzoic acid (16).

Original languageEnglish (US)
Pages (from-to)13363-13369
Number of pages7
JournalChemistrySelect
Volume4
Issue number45
DOIs
StatePublished - Dec 6 2019

Bibliographical note

Funding Information:
Research reported in the publication was fully supported the by the Bill & Melinda Gates Foundation under award number OPP1178119, the National Institutes of Health under award number P51OD011092 and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development under award numbers U54HD055744 and U01HD076542 (GIG). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work would not have been possible without the ONPRC Endocrine Technologies Core, Flow Cytometry Support Core, Surgical Services Unit and the Division of Comparative Medicine.

Funding Information:
Research reported in the publication was fully supported the by the Bill & Melinda Gates Foundation under award number OPP1178119, the National Institutes of Health under award number P51OD011092 and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development under award numbers U54HD055744 and U01HD076542 (GIG). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work would not have been possible without the ONPRC Endocrine Technologies Core, Flow Cytometry Support Core, Surgical Services Unit and the Division of Comparative Medicine .

Publisher Copyright:
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Keywords

  • Cell cycle
  • Inhibitor
  • Meiosis
  • Oocyte
  • WEE kinase

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