Centre for Chemical Biology and Therapeutics - Research-CCBT
Selective modulation of intracellular signaling pathways is a major challenge impeding deeper understanding of the biology of human diseases, as well as their therapy using small-molecule drugs. Thus far, efforts in academia and the pharmaceutical industry have focused largely on the inhibition of enzymes such as protein kinases using ATP-competitive inhibitors. These approaches suffer from the lack of chemical and biological selectivity. Chemically, many ATP-competitive inhibitors exhibit off-target binding owing to structural similarities between the ATP-binding catalytic folds of many protein kinases. Biologically, inhibition of proximal catalytic steps in signal transduction can lead to a wide variety of phenotypic effects.
Signal propagation in pathways initiated by enzymes like protein kinases or ubiquitin ligases occurs through the molecular recognition of site-specific post-translational modifications by distinct protein domains. Indeed, multiple structural mechanisms for such recognition have been identified as being critical for signal propagation in diverse pathways that not only mediate fundamental biological processes from bacteria to man, but are also implicated in the pathogenesis of human diseases. Therefore, the creation of small-molecule chemical tools that target the molecular recognition of site-specific post-translational modifications offers a potentially attractive new approach for the selective modulation of intracellular signaling pathways, which could markedly extend the reach of chemical biology and seed therapeutics development. Our programme aims to explore this concept, with the objective of creating a palette of selective chemical tools that modulate the recognition of site-specific protein phosphorylation by specific domains.