Dynamics of human protein kinase Aurora A linked to drug selectivity.

Warintra Pitsawong,Dorothee Kern,Steffen Kutter,Nadja Kern,Xavier Meniche,Roman V Agafonov,Adelajda Zorba,Ricardo Ap Pádua,Renee Otten,Vanessa Buosi,Gunther Kern

doi:10.7554/elife.36656

Warintra Pitsawong, Dorothee Kern + Show 9 more

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https://doi.org/10.7554/elife.36656

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Abstract

Protein kinases are major drug targets, but the development of highly-selective inhibitors has been challenging due to the similarity of their active sites. The observation of distinct structural states of the fully-conserved Asp-Phe-Gly (DFG) loop has put the concept of conformational selection for the DFG-state at the center of kinase drug discovery. Recently, it was shown that Gleevec selectivity for the Tyr-kinase Abl was instead rooted in conformational changes after drug binding. Here, we investigate whether protein dynamics after binding is a more general paradigm for drug selectivity by characterizing the binding of several approved drugs to the Ser/Thr-kinase Aurora A. Using a combination of biophysical techniques, we propose a universal drug-binding mechanism, that rationalizes selectivity, affinity and long on-target residence time for kinase inhibitors. These new concepts, where protein dynamics in the drug-bound state plays the crucial role, can be applied to inhibitor design of targets outside the kinome.

Highlights

Protein kinases have become the number one drug target of the 21th century (Cohen, 2002; Hopkins & Groom, 2002), due to their central role in cellular processes and involvement in various types of cancer (Carvajal, Tse, & Schwartz, 2006; Gautschi et al, 2008; Katayama & Sen, 2010).Despite their therapeutic significance, the development of specific kinase inhibitors proves to be extremely challenging because they must discriminate between the very similar active sites of a large number of kinases in human cells
An induced-fit step turns out to be key for all tight-binding inhibitors studied
From our results on Aurora A kinase presented here and earlier data on Tyrosine-kinases (Agafonov et al, 2014; Wilson et al, 2015), we propose that this is a general mechanism for different kinases and multiple inhibitors, thereby providing a platform for future computational and experimental efforts in rational drug design

Summary

Introduction

Protein kinases have become the number one drug target of the 21th century (Cohen, 2002; Hopkins & Groom, 2002), due to their central role in cellular processes and involvement in various types of cancer (Carvajal, Tse, & Schwartz, 2006; Gautschi et al, 2008; Katayama & Sen, 2010). Despite their therapeutic significance, the development of specific kinase inhibitors proves to be extremely challenging because they must discriminate between the very similar active sites of a large number of kinases in human cells. It has long been proposed that the conformational state of the fully conserved DFG (for Asp-Phe-Gly) loop (Taylor, Keshwani, Steichen, & Kornev, 2012) dictates the selectivity for Gleevec and other kinase inhibitors (Lovera et al, 2012; Treiber & Shah, 2013).

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