Deciphering the inhibition mechanism of a pseudokinase: integrin-bound kinase and cpd22

Abstract

According to World Health Organization (WHO) cancer is one of top non- infectious death causes worldwide. In this context, as such the searching of new potent and safe anticancer drugs is a hot point for pharmacy industry and academic investigation. Despite protein kinases have been one of the most explored anticancer targets, its evolutionary degenerated parents, pseudokinases, have attracted the attention of scientific community during the last decade. Integrin Linked Kinase (ILK) is a member of the human pseudokinome that has been claimed and validated as a prommissing target for neoplastic diseases. The only well-known ILK inhibitor, CPD22, has probed its activity in phenotypic assays, however very few knowledge regarding its mechanism of action at molecular level is available. Using chemoinformatic and molecular modelling techniques we were able to elucidate if this molecule is able to bind to ILK and how. Additionally, our model explains the SAR raised from the optimization campaign, and SPR experiments have probed, by first time, that this molecule binds to ILK, thus supporting the hypothesis of inhibition by direct binding and the computational model as well.