Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer.

Alex T. Grupenmacher,Tadanori Tomita,Robert A. Horton,Saktimayee M. Roy,Anders W. Bailey,Connor P. Dyer,David R. Piper,Amreena Suri,Alan P. Kozikowski,Maurício T. Tavares,Simone T. Sredni,Hendra Gunosewoyo

doi:10.3390/ijms20092112

Abstract

Polo-like kinase 4 (PLK4) is a cell cycle-regulated protein kinase (PK) recruited at the centrosome in dividing cells. Its overexpression triggers centrosome amplification, which is associated with genetic instability and carcinogenesis. In previous work, we established that PLK4 is overexpressed in pediatric embryonal brain tumors (EBT). We also demonstrated that PLK4 inhibition exerted a cytostatic effect in EBT cells. Here, we examined an array of PK inhibitors (CFI-400945, CFI-400437, centrinone, centrinone-B, R-1530, axitinib, KW-2449, and alisertib) for their potential crossover to PLK4 by comparative structural docking and activity inhibition in multiple established embryonal tumor cell lines (MON, BT-12, BT-16, DAOY, D283). Our analyses demonstrated that: (1) CFI-400437 had the greatest impact overall, but similar to CFI-400945, it is not optimal for brain exposure. Also, their phenotypic anti-cancer impact may, in part, be a consequence of the inhibition of Aurora kinases (AURKs). (2) Centrinone and centrinone B are the most selective PLK4 inhibitors but they are the least likely to penetrate the brain. (3) KW-2449, R-1530 and axitinib are the ones predicted to have moderate-to-good brain penetration. In conclusion, a new selective PLK4 inhibitor with favorable physiochemical properties for optimal brain exposure can be beneficial for the treatment of EBT.

Highlights

Protein kinases (PKs) have the ability to transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues
Alisertib (Figure 2A) and axitinib (Figure 2B) engaged in an additional cation-π interaction with Lys-40, while the empirical structure of centrinone [59] (Figure 2C) and the docking pose of centrinone B (Figure 2D) both engaged in cation–dipole interactions with this residue (−NH3+ F)
The docking findings highlighted the potential of KW-2449 and R1530 to guide further structure–activity relationship (SAR) studies as well as the design of novel compounds with improved exploration of the Polo-like kinase 4 (PLK4) binding cavity

Summary

Introduction

Protein kinases (PKs) have the ability to transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. The human genome encodes 538 PKs. Most of them stimulate cell proliferation, survival, and migration, when constitutively overexpressed and, are associated with human cancer initiation and progression [1]. Targeted cancer therapies with small-molecule protein kinase inhibitors (PKI) have been developed to block molecules that are either upregulated and overexpressed or mutated in tumor cells, minimizing toxicities, while improving treatment effectiveness [1,2]. The STM approach, which is based on selective PKI drug candidates, offers the potential for an improved therapeutic safety index and a potential for better efficacy through treatment with selective PKI drug combinations to address the challenge of tumor heterogeneity

Objectives

Methods

Results

Discussion

Conclusion