The Kinase Chemogenomic Set (KCGS): An Open Science Resource for Kinase Vulnerability Identification.

Carrow Wells ,Stefan Knapp ,Brandon J Turunen ,Stephanie B Hatch ,Nathanael S Gray ,Ivan Đikić ,Christopher R M Asquith ,Michel Michaelides ,William J Zuercher ,Santiago Vilar ,Robert E Futrell ,Alexandra Stolz ,Mariana Edith Tellechea ,Martin Schröder ,Alison D Axtman ,Daniel Ebner ,Ulrich Lücking ,Susanne Müller ,Peter Ettmayer ,Dafydd R Owen ,Jinhua Wang ,Kumar Singh Saikatendu ,Timothy M Willson ,Christian Fischer ,David M Andrews ,Alfredo Picado ,Mathias Frederiksen ,Caitlin E Mills ,Hassan Al-Ali ,David H Drewry

doi:10.3390/ijms22020566

Abstract

We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS), current Version 1.0, is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens.

Highlights

The protein kinases have emerged as one of the most productive families of drug targets in the 21st century
Candidate kinase inhibitors were received from GlaxoSmithKline, Pfizer, Takeda, Abbvie, MSD, Bayer, Boehringer Ingelheim, and AstraZeneca
The results showed that kinase chemogenomic set (KCGS) clogP values trended towards lower lipophilicity than the FDA-approved drugs, with 65% of the KCGS inhibitors falling between consensus logP (cLogP) 2 and 4 and proportionally fewer inhibitors with cLogP > 4 (Figure 3B)

Summary

Introduction

The protein kinases have emerged as one of the most productive families of drug targets in the 21st century. Over 60 small molecule kinase inhibitors have been approved by the FDA since 2001 for the treatment of cancer, inflammation, and fibrosis [1]. Many of these drugs, those that are used in oncology, owe their efficacy to inhibition of multiple kinases [2]. For some targets second- and third-generation inhibitors have been designed to block the activity of mutant kinases that cause drug resistance after first line therapy. These drugs target only a small fraction of the 500+ human kinases. We and others have proposed that the remaining kinases represent an untapped trove of new drug targets [3,4,5]

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Results

Discussion

Conclusion