What is a WEE1 inhibitor?

WEE1 is a key regulator of cell cycle progression at the G2M checkpoint and controls entry into mitosis. AZD1775, a potent WEE1 inhibitor, abrogates WEE1 by phosphorylating and inactivating CDC2 which can force cells to enter mitosis with unrepaired DNA damage (7).

What is AZD1775?

Adavosertib (AZD1775) is a selective inhibitor of Wee1 kinase. Recent preclinical model data additionally show single agent anti-tumor activity in multiple cancer cell lines and tumor xenografts. Preliminary data show AZD1775 is tolerable at lower doses in combination with chemotherapeutic agents.

How do WEE1 inhibitors work?

WEE1 inhibition can increase genomic instability by inducing replication stress and G2/M checkpoint inactivation, which result in increased cellular sensitivity to DNA damaging agents.

How is WEE1 activated?

It is inactivated by phosphorylation through Wee1 and activated by the phosphatase Cdc25C. Cdc25C in turn is activated by Polo kinase and inactivated by Chk1. Thus in S. pombe Wee1 regulation is mainly under the control of phosphorylation through the polarity kinase, Pom1’s, pathway including Cdr2 and Cdr1.

What is the function of Wee1 kinase?

Wee1 Kinase. Wee1 is a nuclear protein involved in the regulation of the G2/M checkpoint by negatively regulating entry into mitosis by catalyzing an inhibitory tyrosine phosphorylation of the Cdc2/cyclin B kinase complex.

Which proteins does Wee1 control?

Wee1 is a protein kinase that regulates the G2 checkpoint and prevents entry into mitosis in response to DNA damage (Fig. 1; ref. 1). The cell cycle is a highly controlled process.

Is Wee1 a tumor suppressor?

Conclusions. These results suggest that, while Wee1 acts as a tumor suppressor in the context of normal cell growth and its functional loss can be compensated by p53-dependent DNA damage repairing mechanisms, specific inhibition of Wee1 has deleterious effects on the proliferation and survival of p53 inactive tumors.

What is the role of Securin?

Securin is also an APC substrate and is known for its role in inactivating the cohesin-cleaving enzyme, separase, until the metaphase to anaphase transition. Here we show that securin has an additional role in cell-cycle regulation, that of modulating the timing of entry into M-phase.

What are the 4 stages of the cell cycle?

In eukaryotes, the cell cycle consists of four discrete phases: G1, S, G2, and M. The S or synthesis phase is when DNA replication occurs, and the M or mitosis phase is when the cell actually divides. The other two phases — G1 and G2, the so-called gap phases — are less dramatic but equally important.

What are Chk1 and Chk2?

Function. Checkpoint kinases (Chks) are protein kinases that are involved in cell cycle control. Two checkpoint kinase subtypes have been identified, Chk1 and Chk2. Chk1 is a central component of genome surveillance pathways and is a key regulator of the cell cycle and cell survival.

Will securin be released from separase?

APC/CCDC20 then targets several proteins including cyclin B and securin to ubiquitin-mediated degradation. Proteolysis of securin releases separase, which in turn cleaves cohesin to allow sister chromatid separation and anaphase.

What initiates spindle assembly?

Just at the beginning of mitosis, both centrioles achieve their maximal length, recruit additional material and their capacity to nucleate microtubules increases. As mitosis progresses, both centrosomes separate to generate the mitotic spindle. In this way, the mitotic spindle has two poles emanating microtubules.