Shifting the Paradigm - Targeting Allosteric Interactions

One of the most rapid and effective ways to modulate activity of proteins in mammalian cells is via post-translational modification, with modifiers ranging from small chemical molecules, such as phosphate, methyl or acetate groups, to protein modifiers, like Ubiquitin, Sumo and Nedd8.

Majority of currently marketed drugs modulate the function of drug targets via binding to their active sites, while the fine-tuned cellular signaling is actually accomplished via selective allosteric (off-catalytic site) interactions, including specific protein-protein interactions, that switch on/off the catalytic activity.

In addition, many key cellular regulators carry out multiple functions, often with the opposite effects on the disease progression - an indiscriminate shutdown of all functions via inhibition of the target’s catalytic activity can lead to non-beneficial effects and lack of therapeutic efficacy.

Despite many successes in anti-cancer drug discovery, toxicity and rapidly developing resistance remain serious issues for majority of drugs currently on market. This in part can be explained by the fact that a common mechanism of drug action is via binding to the target’s active site which is usually conserved throughout the protein family. With hundreds of proteases, kinases and phosphatases in the human proteome, ligands derived against active sites have an inherent selectivity problem manifesting itself in side effects and toxicity.

Only few marketed drugs, discovered serendipitously, have an allosteric mechanism of action, and to date no protein-protein interaction modulators have been developed as clinically useful drugs.

Our team is focusing on the discovery and development of ligands for allosteric and protein-protein interactions. The emphasis on allosteric versus catalytic sites holds a promise for the development of novel selective therapies with fewer side effects and lower toxicity.