Abstract B17: Development of novel, potent orally available Wee1 inhibitors with robust antitumor efficacy in vivo

Abstract:

Wee1 is a tyrosine kinase that phosphorylates cyclin-dependent kinase 1 (CDC2) to inactive the CDC2/cyclinB complex. Wee1 is therefore a key regulator of the cell cycle, maintaining the G2 checkpoint arrest to allow for pre-mitotic repair upon genomic stress. Unlike normal cells, most p53-deficient tumors lack a functional G1 checkpoint and instead rely on the G2 checkpoint for DNA repair. Abrogation of the G2 checkpoint by a Wee1 inhibitor therefore sensitizes p53-deficient tumors to DNA-damaging anticancer agents and enhances their cytotoxic effect. Strong evidence for chemo-sensitization has been demonstrated in multiple pre-clinical models and also in clinical trials. These clinical observations combined with recent reports demonstrating single agent efficacy make Wee1 a promising target for anticancer therapy. With only one inhibitor (AZD1775) in clinical development and very few reports of compounds …

Año de publicación:

2017

Keywords:

Fuente:

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