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PLK
Plk
Plk(2)
PLKs, a family of conserved serine/threonine kinases, are regulators of the cell cycle, wherein they mediate G2/M transitions, activation of cdc25 and mitotic processes including centrosome maturation, bipolar spindle formation, activation of the anaphase-promoting complex (APC), chromosome segregation, actin ring formation (cytokinesis), DNA damage repair pathways, and apoptosis. Plk3 is a multifunctional stress response protein that responses to signals induced by DNA damage and/or mitotic spindle disruption.(1)
The catalytic domain of PLKs is located in the N-terminus. The C-terminus of Plks contains one or two motifs known as polo boxes that help localize the kinase to specific mitotic structures during mitosis. These include the centrosomes in early M phase, the spindle midzone in early and late anaphase and the midbody during cytokinesis. Plk3 substrates include Chk2 and p53.(1)

Drugs/Indications
Trial Drugs/Indications
Generic Code Old Code Brand Company Indication trials
rigosertib ON 01910 SyB L-1101, SyB C-1101 Estybon OncoNova P3: pancreatic, MDS, CML; P2: ovarian, HNN, anal; P1/2: ALL; P1: solid, HCC, MCL, ALL trials
volasertib BI 6727 Boehringer Ingelheim P3: AML; P2: ovarian, NSCLC, urothelial, solid; P1: leukemia trials
TKM-080301 Tekmira P1/2:NET, adrenocortical, HCC; P1: CRC, pancreatic, gastric, BC, ovarian trials
cafusertib Jiangsu P1: AML, solid trials
CFI-440945 Noncorporate P1: various trials
Failed Drugs
Generic Code Old Code Brand Company Indication trials
BI 2536 Boehringer Ingelheim Last new trial started in 2007; P2: AML, SCLC, NSCLC, pancreatic, BC, endometrial, HNN, melanoma, ovarian, sarcoma; P1: lymphoma trials
GSK461364 GSK Last new trial started in 2007; P1: solid trials
MK-1496 Merck Last trial started in 2009; P1: solid trials
NMS-1286937 NMS-P937 Nerviano Last trial started in 2009; P1: solid trials


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References

1. Polo-like_kinase. [cited]; Available from: http://en.wikipedia.org/wiki/Polo-like_kinase.

2. Xie S, Xie B, Lee MY, Dai W. Regulation of cell cycle checkpoints by polo-like kinases. Oncogene. 2005;24(2):277-86.



News
Thursday, September 1, 2016 3:00 PM|Bioorganic and Medicinal Chemistry Letters|Bioorganic and Medicinal Chemistry Letters via MedWorm.com|Comments|Labels: PLK
Authors: Zhao XZ, Hymel D, Burke TR Abstract By a process involving initial screening of a set of 87 aldehydes using an oxime ligation-based strategy, we were able to achieve a several-fold affinity enhancement over one of the most potent previously known polo-like kinase 1 (Plk1) polo-box domain (PBD) binding inhibitors. This improved binding may result by accessing a newly identified auxiliary region proximal to a key hydrophobic cryptic pocket on the surface of the protein. Our findings could have general applicability to the design of PBD-binding antagonists. PMID: 27624074 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry Letters)
Friday, August 26, 2016 1:20 PM|Elsevier|JournalTOCs API - Biochemical and Biophysical Research Communications (50 articles)|Labels: PLK, lung cancer

MiR-509-3-5p causes aberrant mitosis and anti-proliferative effect by suppression of PLK1 in human lung cancer A549 cells

Biochemical and Biophysical Research Communications, Vol. , No. (2016) pp. -
Publication date: 16 September 2016 Source:Biochemical and Biophysical Research Communications, Volume 478, Issue 2 Author(s): Xian-Hui Wang, Yao Lu, Jing-Jing Liang, Ji-Xiang Cao, Ya-Qiong Jin, Guo-Shun An, Ju-Hua Ni, Hong-Ti Jia, Shu-Yan Li MicroRNAs (miRNAs) are potent post-transcriptional regulators of gene expression and play roles in DNA damage response (DDR). PLK1 is identified as a modulator of DNA damage checkpoint. Although down-regulation of PLK1 by certain microRNAs has been reported, little is known about the interplay between PLK1 and miR-509-3-5p in DDR. Here we have demonstrated that miR-509-3-5p repressed PLK1 expression by targeting PLK1 3′-UTR, thereby causing mitotic aberration and growth arrest of human lung cancer A549 cells. Repression of PLK1 by miR-509-3-5p was further evidenced by over-expression of miR-509-3-5p in A549, HepG2 and HCT116p53−/− cancer cells, in which PLK1 protein was suppressed. Consistently, miR-509-3-5p was stimulated, while PLK1 protein was down-regulated in A549 cells exposed to CIS and ADR, suggesting that suppression of PLK1 by miR-509-3-5p is a component of CIS/ADR-induced DDR pathway. Flow cytometry and immunofluorescence labeling showed that over-expression of miR-509-3-5p in A549 induced G2/M arrest and aberrant mitosis characterized by abnormal bipolar mitotic spindles, condensed chromosomes, lagging DNA and chromosome bridges. In addition, over-expression of miR-509-3-5p markedly blocked A549 cell proliferation and sensitized the cells to CIS and ADR treatment. Taken together, miR-509-3-5p is a feasible suppressor for cancer by targeting PLK1. Our data may provide aid in potential design of combined chemotherapy and in our better understanding of the roles of microRNAs in response to DNA damage.

Monday, August 1, 2016 1:00 AM|Leisner, T. M., Freeman, T. C., Black, J. L., Parise, L. V.|The FASEB Journal recent issues|Labels: INT, PLK

Calcium- and integrin-binding protein 1 (CIB1) is a small, ubiquitously expressed protein that was first identified as an intracellular binding partner of a platelet-specific α-integrin cytoplasmic tail. Although early studies revealed a role for CIB1 in regulating platelet integrin activity, recent studies have indicated a more diverse role for CIB1 in many different cell types and processes, including calcium signaling, migration, adhesion, proliferation, and survival. Increasing evidence also points to a novel role for CIB1 in cancer and cardiovascular disease. In addition, an array of CIB1 binding partners has been identified that provide important insight into how CIB1 may regulate these processes. Some of these binding partners include the serine/threonine kinases, p21-activated kinase 1 (PAK1), apoptosis signal-regulating kinase 1 (ASK1), and polo-like kinase 3 (PLK3). Structural and mutational studies indicate that CIB1 binds most or all of its partners via a well-defined hydrophobic cleft. Although CIB1 itself lacks known enzymatic activity, it supports the PI3K/AKT and MEK/ERK oncogenic signaling pathways, in part, by directly modulating enzymes in these pathways. In this review, we discuss our current understanding of CIB1 and key questions regarding structure and function and how this seemingly diminutive protein impacts important signaling pathways and cellular processes in human health and disease.—Leisner, T. M., Freeman, T. C., Black, J. L., Parise, L. V. CIB1: a small protein with big ambitions.

Wednesday, May 11, 2016 3:00 PM|Current Pharmaceutical Design|Current Pharmaceutical Design via MedWorm.com|Comments|Labels: PLK, sarcoma
Authors: Cheng L, Wang C, Jing J Abstract Osteosarcoma is the most common type of pri¬mary bone tumor in adolescents and young adults. The dysregulation of cell cycle control and cell division often results in the aberrant growth of osteosarcoma cells. The primary proteins involved in cell cycle control and cell division include checkpoint kinases (CHKs), cyclin-dependent kinases (CDKs), polo-like kinases (PLKs) and aurora kinases (AURKs). In recent years, a large number of these protein kinase inhibitors have been identified in osteosarcoma. In this review, we highlight the current drugs being developed to target these protein kinases in osteosarcoma. PMID: 27174724 [PubMed - as supplied by publisher] (Source: Current Pharmaceutical Design)
Sunday, February 28, 2016 4:00 PM|Molecular Cancer Research|MedWorm: Cancer Therapy|Comments|Labels: PLK, breast cancer
We reported recently that a loss of Plk2 in the developing mammary gland results in increased proliferation, hyperbranching, misoriented mitotic spindle assembly and defects in polarity (Villegas et al Development 2015). Loss of Plk2 was accompanied by increased expression of Plk1. Genetic rescue experiments, knocking down Plk1 in Plk2 null mouse mammary epithelium, and bimolecular fluorescence complementation assays, using wildtype Plk2 and a kinase dead mutant (KD) of Plk2 as bait, revealed that Plk2 regulates these processes through its direct interaction with Plk1. Our preliminary data suggest that loss of Plk2 results in increased Plk1 protein but not RNA expression. We propose that Plk2 functions as a tumor suppressor by decreasing Plk1 stability in TNBCs. Loss of Plk2, therefore, ma...