The Juxtaposition of Allosteric and Catalytic Inhibition in PLK1: Tradeoff for Chemotherapy and Thermodynamic Profiles of KBJK557 and BI 6727

Abstract

Polo-like kinase 1 (PLK1) is a serine/threonine kinase cell cycle modulator and a highly significant biomarker in chemotherapy. Cancer treatment strategies now prioritize PLK1-inhibitor-based drugs that target either the catalytic (kinase) or regulatory (polo-box) domains. Comparative studies on PLK1 are needed to highlight the tradeoff between catalytic- and allosteric-based inhibition. We report the first study on PLK1 binding kinetics using KBJK557, a potent small-molecule scaffold for “allosteric” inhibition and volasertib (BI 6727), a phase III approved drug for “catalytic” inhibition. The binding landscape of polo-box domain (PBD) was found to be fairly preserved with a higher binding free energy (-31.00 kcal/mol) than kinase domain (KD) (–29.40 kcal/mol). Noncovalent bond interactions were found to differ for individual inhibitors, mainly stronger hydrogen bonds for KBJK557 and weaker electrostatic bonds for volasertib. Interestingly, the noncovalent bond interactions of volasertib were largely dependent on PBD residues. Volasertib was found to induce structural stability in PLK1 as though in a ‘cooperative manner’, whereas KBJK557 induced structural flexibility. The results from our study provide underpinnings for cooperative binding studies in PLK1 and will be useful for future research to develop both PBD and KD as well as dual-functional inhibitors against PLK1.