2. Academic Validation
  3. Selective Wee1 Inhibitors Led to Antitumor Activity In Vitro and Correlated with Myelosuppression

Selective Wee1 Inhibitors Led to Antitumor Activity In Vitro and Correlated with Myelosuppression

  • ACS Med Chem Lett. 2023 Apr 7;14(5):566-576. doi: 10.1021/acsmedchemlett.2c00481.
Satenig Guler 1,  Maria C DiPoto 1,  Alejandro Crespo 1,  Richard Caldwell 1,  Benjamin Doerfel 2,  Nina Grossmann 2,  Kevin Ho 1,  Bayard Huck 1,  Christopher Cv Jones 1,  Ruoxi Lan 1,  Djordje Musil 2,  Justin Potnick 1,  Heike Schilke 2,  Brian Sherer 1,  Stephanie Simon 2,  Christian Sirrenberg 2,  Zhuo Zhang 1,  Lesley Liu-Bujalski 1
Affiliations

Affiliations

  • 1 EMD Serono, Billerica, Massachusetts 01821, United States.
  • 2 Merck Healthcare KGaA, 64293 Darmstadt, Germany.
PMID: 37197456 DOI: 10.1021/acsmedchemlett.2c00481
Abstract

Wee1 is a tyrosine kinase that is highly expressed in several Cancer types. Wee1 inhibition can lead to suppression of tumor cell proliferation and sensitization of cells to the effects of DNA-damaging agents. AZD1775 is a nonselective Wee1 Inhibitor for which myelosuppression has been observed as a dose-limiting toxicity. We have applied structure-based drug design (SBDD) to rapidly generate highly selective Wee1 inhibitors that demonstrate better selectivity than AZD1775 against PLK1, which is known to cause myelosuppression (including thrombocytopenia) when inhibited. While selective Wee1 inhibitors described herein still achieved in vitro antitumor efficacy, thrombocytopenia was still observed in vitro.

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