Drug Discovery


KINASES – old dogs


and new tricks application of new assay technologies to shed light on kinase drug discovery


The human kinome comprises 518 known protein kinases and more than 20 lipid kinases. Nearly all aspects of control within a cell are modulated by reversible phosphorylation of proteins, mediated by protein kinases.


A


bnormal phosphorylation is a cause or effect of many diseases including cancer and inflammatory diseases, hence many


pharma and biotech companies continue to under- take research and development in this area believ- ing it to be of clinical importance. While we can congratulate ourselves on our success in identifying more than 37 kinase inhibitor compounds that have made it to patients and more than 250 drug candidates that are undergoing clinical evaluation, arguably we have only scratched the surface of kinase biology. A seminal paper1 published in Science in December 2017 provides an interesting insight into drug discovery within the kinome space and, to use the space analogy, helps us to realise that at best we have only explored our own kinase solar system, let alone our galaxy and what lies beyond in kinome space. Within the paper, Klaeger et al used a chemical


proteomic approach (using kinobeads) and quan- titative mass spectrometry to characterise the drug discovery space of 243 clinical kinase inhibitors that are either approved drugs or have been tested in humans across a wide variety of protein kinas-


Drug Discovery World Spring 2018


es. Interestingly, although many kinase inhibitors are claimed to be both potent and selective, the majority are not, resulting in failures in the clinic and obstacles to the use of these compounds in basic research as tools to investigate kinase biolo- gy. Selectivity does not appear to correlate with clinical efficacy or safety. Some compounds such as rabusertib, a very selective CHEK1 inhibitor, show exquisite selectivity (rabusertib was devel- oped by Eli Lilly but dropped due to its apparent lack of activity in any clinical setting). Other examples of selective inhibitors include capma- tinib for MET and lapatinib for EGFR. However, many more inhibitors are less selective, targeting more than 100 kinases simultaneously and mak- ing it impossible to attribute a specific inhibitor activity to a particular clinical outcome. Of the 243 compounds examined in this paper, approxi- mately 15% were reasonably selective, but selec- tivity decreased rapidly to a class of almost non- selective compounds such as midostaurin and XL- 228, interestingly with approved and non- approved clinical candidates at both ends of this selectivity spectrum.


By Dr Gary Allenby


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