Many protein kinases are targeted by therapeutics in human diseases, including cancer, but their mechanism of action goes way beyond inhibiting a single kinase. The overwhelming majority of small molecule kinase inhibitors exhibit substantial multi-target pharmacology regardless of their sub-type (type 1, type 2, etc.), which means that a single agent affects many targets simultaneously at therapeutic concentrations. We analyzed multiple data sources to find a realistic estimate of the extent of multi-target pharmacology for all approved cancer drugs and demonstrated that at therapeutic concentrations the range of the number of targets affected by the (initially) kinase-targeting drugs ranges from several targets to several hundred ones. It includes includes inhibitors trapping kinases in an inactive (aka DFG-out) state like Imatinib and Nilotinib. The 'off'-targets also include unexpected essential pathways, including the Hedgehog pathway. The detailed analysis is presented along with the effect of expression levels on the drug targeting profile. The specificity can be somewhat increased, but not to the level of a single target, if the targeted pocket is an allosteric site. In collaboration with Dr. C.Cochet laboratory, Grenoble, two laboratories from University of Lyon, M.Engel lab in Saarland Uni., I.Kufareva, UCSD, and P.Brear laboratory from Cambridge, UK, we identified new small molecules that modulate activity of casein kinase 2 in substrate-selective manner by binding to the interface between subunits α and β. We expect that in the future the multitarget pharmacology of kinase inhibitors will be extended and the design goals will be including a complex kinase profile as recently proposed in the "DREAM challenge".

Multi-target pharmacology of kinase inhibitors, beneficial off-targets and allosteric sites

2019 Fall National Meeting

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