Innovating Your Drug Discovery

An Expanding Chemogenomic Toolbox Gives Kinome Research a Welcome and Much Needed Boost

The human kinome includes 500+ druggable targets, with 35+ small molecule kinase inhibitors approved by the FDA since 2000. Remarkable. Despite the clinical success of these inhibitors, the number of therapeutically validated kinase targets remains small, and as of 2010 only 20 percent of the kinome had been functionally characterized, or “well-studied” [1]. Unfortunately, research over the past seven years has done little to improve significantly the number of well-studied kinases and validated targets. As such, the sandbox for kinase inhibitor drug discovery remains relatively small and is certainly not dynamic. Significant focus is spent on next generation inhibitors for existing validated targets, inhibitors for clinical resistance mutants, and combinations of approved kinase drugs. These are all worthy initiatives that benefit patients and make sense for drug discovery companies from an economic perspective. Nevertheless, the kinase field remains trapped in a local minimum, and additional tools and research paradigms are required to tap therapeutic value from the remaining 80 percent of the kinome.

A recent study published in PLOS ONE by the Structural Genomics Consortium (SGC), a public-private partnership, gives new hope for expanding the sandbox of therapeutically relevant kinases. This paper describes significant progress toward the development of a comprehensive, publicly available Kinase Chemogenomic Set (KCGS) that shall address two unmet needs in the field:

  • Availability of annotated and selective “narrow spectrum” kinase inhibitor tools for the understudied kinome.
  • A mechanism for crowd-sourcing these tools to the larger community to enable broad testing across diverse disease models.

The KCGS was created by assembling and testing large numbers of published compounds contributed by several pharmaceutical partners, and only compounds passing stringent potency and kinome-wide selectivity metrics are included. The strict selectivity requirement, where only narrow spectrum inhibitors are included, and the fact that all included compounds are annotated across a significant fraction of the kinome, give this set significant value and differentiates it from many commercially available compounds and compound collections where the degree of annotation is often minimal, incomplete, or not reported. Indeed, an outstanding recent perspective on the use and misuse of chemical probes highlights the deleterious and lasting ramifications of using poorly annotated chemical probes for target discovery and validation [2].

New data reported in the PLOS ONE publication are mainly focused on the complete kinome-wide annotation of “PKIS2”, a 645-member kinase inhibitor collection representing 86 diverse chemotypes that augment the SGC’s initial PKIS collection [3]. Comprehensive DiscoverX KINOMEscan® data across PKIS2 were collected rapidly and with a low false positive rate (0.5%), which enabled the SGC team to move quickly and to gather the largest publicly available dataset annotating a large compound collection. The PKIS2 KINOMEscan screen identified 174 narrow spectrum compounds (23 chemotypes) that cover 81 kinases. Version 1 of the KCGS, which shall include these PKIS2 compounds, PKIS compounds, and compounds identified from the literature, is slated to be shared with the research community in 2018 and is anticipated to include potent, narrow spectrum inhibitors for well over 200 kinases. With this new tool set in hand and a mechanism in place for crowd-sourced testing, the future should be bright for unveiling valuable new therapeutic kinase targets.



  1. Fedorov O, Müller S, Knapp S. The (un)targeted cancer kinome. Nat Chem Biol. (2010) 6:166-169.
  2. Blagg J and Workman P. Choose and use your chemical probe wisely to explore cancer biology. Cancer Cell. (2017) 32:9-25.
  3. Elkins, J M et al. Comprehensive characterization of the Published Kinase Inhibitor Set. Nat Biotechnol. (2016) 34:95–103.