The Department of Biomedicine

BBB Seminar: Richard Alan Engh

Rationalizing protein kinase inhibitor selectivity profiles

Richard Alan Engh,
The Norwegian Structural Biology Centre, Department of Chemistry, University of Tromsø

Therapeutic protein kinase inhibition is now well validated by the success of a series of compounds approved for use over the last ten years. This answers early skepticism that adequate selective inhibition of disease targets would be possible to achieve. Despite the successes, however, selectivity remains a critical parameter, and a solid understanding of the factors relevant to selectivity is a key to efficient drug discovery. With high throughput synthesis, screening, and structural analysis capabilities, modern drug discovery tools also provide a wealth of information for analysing selectivity factors. Studies show how protein kinases differ in highly diverse ways, due to the requirements for stringent activity control in cell signalling. Protein kinase inhibitor design strategies make use of these differences, which include single amino acid replacements, refolding events, posttranslational modifications, and diverse domain-domain and co-factor interactions. This talk presents an overview of protein kinase inhibitor selectivity properties, illustrated by case studies of individual selectivity determinants and applications to drug discovery.

Host: Aurora Martinez, Department of Biomedicine