Protein kinases, enzymes that phosphorylate proteins and other organic molecules, are increasingly important targets for drug discovery.
Inhibiting these enzymes can disrupt signal-transduction pathways that play a critical role in a variety of disorders, particularly cancer and inflammatory diseases.
At CHI’s recent “Next-Gen Kinase Inhibitors” conference, presenters discussed recent advances and ongoing challenges in targeting kinases for drug discovery. Examples of the innovative work described include novel screening methods to quantify protein-protein interactions in live cell-based screening systems, approaches for selective targeting of protein kinases, and design strategies for generating potent kinase inhibitors.
As a target class, kinases have “proven to be highly druggable and a rich source of clinical agents and approved therapies, some of which have been identified using relatively new approaches such as fragment-based design,” said James E. Dowling, Ph.D., principal scientist at AstraZeneca’s R&D Boston facility. “These accomplishments are quite impressive given the early views of many scientists who felt that the conserved ATP-binding pocket would present a challenge to the identification of selective inhibitors.”
As with all drug candidates, balancing factors such as potency, selectivity for the target, off-target effects, bioavailability, pharmacokinetics, and other drug-like properties is a challenge in the development of kinase inhibitors as therapeutic agents.
In the early stages of drug discovery, potency and chemical diversity are perhaps most important. “We also monitor parameters such as solubility, in vitro metabolic stability, and lipophilicity, and we use these parameters to help rank emerging chemical series,” said Dr. Dowling. “There tends to be a willingness to embrace emerging series with potential selectivity issues as long as there are strategies available for increasing primary target potency without simultaneously enhancing off-target effects. Another early objective is to identify early probe compounds with sufficient selectivity to enable successful validation of the target of interest.”