Monday, September 7, 2015

Drugs in Clinical Pipeline: GSK461364A | Polo Kinase Inhibitor | PLK1 Inhibitor | Cancer Drug

GSK461364A [(R)-5-(6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-1-yl)-3-(1-(2-(trifluoromethyl)phenyl)ethoxy)thiophene-2-carboxamide] is a potent, selective, reversible, ATP-competitive inhibitor of Polo-like kinase 1 (Plk1) with a prolonged rate of dissociation from the enzyme. When evaluated against full-length Plk1 in an in vitro biochemical assay, inclusion of a 60-minute preincubation step significantly increased the compound potency, suggesting a time-dependent mechanism of inhibition with an apparent dissociation constant (Ki*app) value of less than 0.5 ± 0.1 nM.

GSK461364A: 2D and 3D Structure

Upon rapid dilution of a preformed enzyme-inhibitor complex into a substrate mix with saturating ATP, a qualitatively slow recovery of activity was observed, indicating that the dissociation of the compound was reversible although not instantaneous and confirming the observed time-dependent inhibition. These data also confirm that the true potency for Plk1 could be substantially lower than its Ki*app determined.

When evaluated against other isoforms of Polo kinase namely Plk2 and Plk3, GSK461364A was significantly less potent (Ki*app value 860 and 1000 nM, respectively). To further explore selectivity, GSK461364A was tested against an in-house panel of 48 kinases. GSK461364A had at least 1000-fold selectivity for Plk1 over the majority of kinases tested. GSK461364A was further screened against a commercial panel of recombinant kinases (KinaseProfiler, Millipore). In this screen, 37 of 262 kinases showed greater than 50% inhibition with only six kinases (PIM-1, PRK2, RSK4, RSK2, RSK3, PDGFRA (V561D)) inhibited by greater than 90% at 10 ┬ÁM (more than 5000-fold of the IC50 for Plk1) [1].

Common Name: GSK461364A
Synonyms: GSK461364A; GSK 461364A; GSK-461364A
IUPAC Name: (R)-5-(6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-1-yl)-3-(1-(2-(trifluoromethyl)phenyl)ethoxy)thiophene-2-carboxamide
CAS Number: 929095-18-1
Mechanism of Action: Kinase Inhibitor; PLK1 Inhibitor; Polo-like Kinase 1 Inhibitor
Indication: Various Cancers
Development Stage: Phase I
Company: GlaxoSmithKline

1H NMR (Estimated) for GSK461364A

What is Polo Kinase?

Polo-like kinase 1 (Plk1) is a conserved ser/thr kinase that plays a critical role during multiple stages of cell cycle progression. In humans, Plk1 is expressed primarily during late G2 and M phases, where it appears to regulate many processes involved in mitotic entry and progression. Plk1 overexpression is strongly associated with cancer and has been correlated with poor prognosis in a broad range of human tumor types. Several studies have demonstrated the essential role of Plk1 in mitotic events, and many protein substrates have been identified. For example, overexpression of Plk1 by transfection results in multinucleation and can also override the G2 arrest checkpoint induced by DNA damage. It has also been shown to have specific roles in centrosome maturation, microtubule dynamics, chromatid separation and cytokinesis. In addition to its mitotic regulation, Plk1 has been reported to phosphorylate the p53 tumor-suppressor causing inhibition of pro-apoptotic p53 function. Thus, Plk1 is a prime target for drug discovery in proliferative diseases such as cancer [2].

1. Gilmartin, A. G.; et. al. Distinct concentration-dependent effects of the polo-like kinase 1-specific inhibitor GSK461364A, including differential effect on apoptosis. Cancer Res 2009, 69(17), 6969-6977.
2. Laquerre, S.; et. al. A potent and selective Polo-like kinase 1 (Plk1) Inhibitor (GSK461364) induces cell cycle arrest and growth inhibition of cancer cell. Cancer Res 2007 67: Abstract 5389.