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 journalArticle

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
Publication statusPublished - Dec 6 2019

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Keywords

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

ASJC Scopus subject areas

  • Chemistry(all)

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