Allosteric drugs targeting Aurora kinases for the treatment of cancer
Pharmacology
Final Report Abstract
In summary, our work defined several findings that may be applicable more widely to the field of protein kinases and drug development to different groups of protein kinases: 1- Allosteric modulators can affect multiprotein complexes and inhibit signaling without inhibiting the catalytic activity of kinases. 2- Compounds binding to the ATP-binding site can also produce important different “reverse allosterc” modulations of multiprotein complexes that affect signaling and presumably clinical outcome. 3- Based on 1- and 2- we also conclude that compounds that bind at the ATP-binding site and produce relevant “reverse allosteric” effects, may inhibit the cellular activity of the kinase even after dissociating from the target. Depending on the constants of each compound to the target, the “retention time” on the target could devine the extent of delocalization of the kinase and may be critical parameter to achieve full inhibition even after dissociation from the target. 4- Once the target is delocalized, the target molecule may become physiologically inactive. In this manner, compounds with such mechanism of action would permanently inhibt the target, even long after dissociation. Exploiting of the above finding should enable to decrease enormously the concentration of drugs in patients. For example, trials using MLN8237 may require considerably less concentration of the drug then typically required to fully inhibit Aurora kinases in vitro. We can further speculate that the lower concentrations of drugs would diminish off-target effects. Thus, we hope that the results of our work help to understand the biology of allosteric regulation of kinases and in addition, provide new clues on how to better target protein kinases for the treatment of patients.
