The GSK461364 PLK1 inhibitor exhibits strong antitumoral activity in preclinical neuroblastoma models

Abstract
Polo-like kinase 1 (PLK1) is a serine/threonine kinase that facilitates the transition from G2 to M phase of the cell cycle. It is overexpressed in high-risk neuroblastomas and is associated with poor patient outcomes. Recent studies, including our own, have highlighted PLK1 as a promising drug target for neuroblastoma, with the PLK1 inhibitor BI2536 demonstrating anti-tumor activity in preclinical models. In this study, we evaluated the effects of GSK461364, a competitive ATP-binding inhibitor of PLK1, on key tumorigenic properties in preclinical in vitro and in vivo neuroblastoma models. Treatment with GSK461364 led to decreased cell viability and proliferation, cell cycle arrest, and a significant increase in apoptosis, all at low nanomolar concentrations and regardless of MYCN copy number status. Furthermore, GSK461364 significantly delayed tumor growth in established xenografts in nude mice and increased survival time for treated animals. These preclinical results suggest that PLK1 inhibitors could be a viable treatment option for patients with high-risk or relapsed neuroblastomas characterized by elevated PLK1 GSK461364 expression and warrant consideration for early-phase clinical trials in pediatric populations.