The kinases, Chk1, Wee1, and Myt1 are key regulators of the G2 checkpoint, which act directly or indirectly to inhibit Cdc2 activity. Show that RNA interference (RNAi)-mediated downregulation of Wee1 kinase abrogated an Adriamycin trade mark -induced G2 checkpoint in human cervical carcinoma Hela cells that are defective in G1 checkpoint response. Wee1 downregulation sensitized HeLa cells to Adriamycin-induced apoptosis.

G2 checkpoint abrogation by PD0166285 was demonstrated to kill cancer cells, there at a toxic highest dose of 0.5 muM in some cell lines for exposure periods of no longer than 6 hours. The deregulated cell cycle progression may have ultimately damaged the cancer cells. Used in mouse melanoma cell line model.

The inhibition of Wee1 kinase by a selective small molecule inhibitor significantly enhances the anti-tumor efficacy of DNA damaging agents, specifically in p53 negative tumors by abrogating S-G2 checkpoints, while normal cells with wild-type p53 are not severely damaged due to the intact function of the G1 checkpoint mediated by p53. Since the measurement of mRNA expression requires a very small amount of biopsy tissue and is highly quantitative, the development of a pharmacodynamic (PD) biomarker leveraging mRNA expression is eagerly anticipated in order to estimate target engagement of anti-cancer agents.

MK-1775 is a first in class Wee1 inhibitor that is well tolerated and shows promising anti-tumor activity in previously treated pts.

Wee1 is a tyrosine kinase that phosphorylates and inactivates CDC2 and is involved in G2 checkpoint signaling. Reported the discovery of a potent and selective small-molecule inhibitor of Wee1 kinase, MK-1775. This compound inhibits phosphorylation of CDC2 at Tyr15 (CDC2Y15), a direct substrate of Wee1 kinase in cells. The data indicate that Wee1 inhibition provides a new approach for treatment of multiple human malignancies.