GSK461364 is a potent and reversible ATP competitive Plk1 inhibitor. Polo-like kinases (Plk) are a family of serine threonine kinases that are critical regulators of DNA damage response and cell cycle progression.
In vitro: GSK461364 showed at least 390-fold greater selectivity for Plk1 than for Plk2 and Plk3 and 1,000-fold greater than for 48 other kinases. The drug showed antiproliferative activity against multiple (>120) tumor cell lines and potently inhibited the proliferation of greater than 83% and 91% of these cell lines [1].
In vivo: Intraperitoneal administration of GSK461364 caused regression or tumor growth delay in different xenograft models. In vivo suppression of Plk1 by using GSK461364 resulted in mitotic arrest with aberrant mitotic figures consisting of monopolar or collapsed mitotic spindles [1].
Clinical trial: The final recommended phase II dose for GSK461364 was 225 mg administered intravenously. Moreover, GSK461364 was suggested to involve coadministration of prophylactic anticoagulation for further clinical evaluation [1].
Reference:
[1] Olmos D, Barker D, Sharma R, Brunetto AT, Yap TA, Taegtmeyer AB, Barriuso J, Medani H, Degenhardt YY, Allred AJ, Smith DA, Murray SC, Lampkin TA, Dar MM, Wilson R, de Bono JS, Blagden SP. Phase I study of GSK461364, a specific and competitive Polo-like kinase 1 inhibitor, in patients with advanced solid malignancies. Clin Cancer Res. 2011 May 15;17(10):3420-30.