Rabbit Anti-Human WEE1 (Phospho-Ser642) polyclonal antibody

Genomically unstable cancers are dependent on specific cell cycle checkpoints to maintain viability and prevent apoptosis. The cell cycle checkpoint protein WEE1 is highly expressed in genomically unstable cancers, including diffuse large B-cell lymphoma (DLBCL). Although WEE1 inhibition effectively induces apoptosis in cancer cells, the effect of WEE1 inhibition on anti-apoptotic dependency is not well understood. We show that inhibition of WEE1 by AZD1775 induces DNA damage and pre-mitotic entry in DLBCL, thereby enhancing dependency on BCL-2 and/or MCL-1. Combining AZD1775 with anti-apoptotic inhibitors such as venetoclax (BCL-2i) or S63845 (MCL-1i) enhanced sensitivity in a cell-specific manner. In addition, we demonstrate that both G2/M cell cycle arrest and DNA damage induction put a similar stress on DLBCL cells, thereby enhancing anti-apoptotic dependency. Therefore, genotoxic or cell cycle disrupting agents combined with specific anti-apoptotic inhibitors may be very effective in genomic unstable cancers such as DLBCL and therefore warrants further clinical evaluation.

Wee1 kinase plays an important role in regulating G2/M checkpoint and S phase, and the inhibition of it will lead to mitotic catastrophe in cancer cells with p53 mutation or deletion. Therefore, the mechanism of Wee1 kinase in cancer treatment and the development of its inhibitors have become a research hotspot. However, although a variety of Wee1 inhibitors with different scaffolds and considerable activity have been successfully identified, so far no one has systematically summarized the structure-activity relationships (SARs) of Wee1 inhibitors. Previous reviews mainly focused on its mechanism and clinical application. To facilitate the rational design and development of Wee1 inhibitors in the future, this paper systematically summarizes its structural types, SARs and binding modes according to the Wee1 inhibitors reported in scientific journals, and also summarizes the regulatory effect of Wee1 kinase on cell cycle and the progress of its inhibitors in clinical application. (C) 2020 Elsevier Masson SAS. All rights reserved.