Polo-like Kinase (PLK)

Polo-like kinases play critical roles during multiple stages of cell cycle progression. All Polo-like kinases contain an N-terminal Ser/Thr kinase catalytic domain and a C-terminal region that contains one or two Polo-boxes. For Polo-like kinase 1, 2, and 3, and their homologs, the entire C-terminal region, including both Polo-boxes, functions as a single modular phosphoserine/threonine-binding domain known as the Polo-box domain (PBD).

1034616-18-6
NMS-1286937
1034616-18-6
1052532-15-6
SBE-13 HCl
1052532-15-6
1062243-51-9
Ro5203280
1062243-51-9
TC-S 7005
1082739-92-1
1137868-52-0
TAK-960
1137868-52-0
1137868-96-2
TAK-960 hydrochloride
1137868-96-2
Rigosertib sodium
1225497-78-8
1228960-69-7
MLN0905
1228960-69-7
ON1231320
131247-39-8
1338806-76-0
CFI-400945
1338806-76-0
1616420-30-4
CFI-400945 Fumarate
1616420-30-4
173529-46-9
HMN-214
173529-46-9
Centrinone
1798871-30-3
Centrinone B
1798871-31-4

Background


An overview of PLKs

Polo-like kinases (PLKs) are a group of highly conserved serine/threonine protein kinases that play a key role in processes such as cell division and checkpoint regulation of mitosis. The activity of these kinases has been shown to be required for regulating multiple stages of mitotic progression in somatic cells. Plks are increasingly considered as key regulators of meiosis, mitosis, and cytokinesis.

Major types of PLKs

PLKs are a group of highly conserved serine/threonine protein kinases. In mammals, four members of the family have been identified (i.e., PLK1, PLK2, PLK3, and PLK4). All PLK members have similar structural features, namely, a conserved NH2-terminal serine/threonine kinase domain and a COOH-terminal regulatory domain consisting of one (as found in PLK4) or two (as found in PLK1, PLK2, PLK3) polo-boxes.

Inhibition of PLKs

PLK inhibitors interfere with different stages of mitosis, such as centrosome maturation, spindle formation, chromosome separation, and cytokinesis. They induce mitotic chaos and severely perturb cell cycle progression, eventually leading to cancer cell death. Several PLK inhibitors are in development and are undergoing evaluations as potential cancer treatments. Numerous PLK inhibitors are in development to evaluate their potential as treatments in oncology. BI 2536, a dihydropteridinone derivative, is a first-in-class prototype PLK1 inhibitor. BI 2536, an ATP-competitive kinase inhibitor, causes perturbation of the spindle assembly, leading to mitotic arrest and subsequent apoptosis. BI 6727 is the second-in-class dihydropteridinone derivative developed by Boehringer Ingelheim. BI 6727 is a potent and selective inhibitor of PLK. It binds to the ATP-binding pocket of the kinase and induces the formation of monopolar spindles.

PLKs and diseases

About 80% of human tumors, of various origins, express high levels of PLK transcripts. However, PLK mRNA is mostly absent in surrounding healthy tissues. Overexpression of PLK is associated with a poor prognosis in several tumor types and a lower overall survival rate. The overexpression of PLKs in human tumors, but not in healthy nondividing cells, makes them an attractive, selective target for cancer drug development.

Reference:

PATRICK SCHÖFFSKI (2009). Polo-Like Kinase (PLK) Inhibitors in Preclinical and Early Clinical Development in Oncology, 14,559-570.