Structure-aided discovery of kinase inhibitors as targeted therapeutic agents for breast cancer

Kinases are important targets for blocking cancer progression. However, many remain to be exploited. For example, no drugs are yet available to specifically inhibit any kinase which is switched on by a regulatory protein called calmodulin. Nonetheless, faulty expression of these “CaMK” enzymes is now thought to play a key role in breast cancer progression. The Wellcome Trust has funded the CAMSEED consortium to discover small molecule inhibitors for a CaMK protein involved in basal-like breast cancer. The three dimensional structure of this target has been solved by the Structural Genomics Consortium and Professor Stefan Knapp at the University of Oxford. Interactions with small molecules are being screened by Professor Michael Overduin’s lab at the University of Birmingham using superconducting magnets and high throughput robots at the national HWB-NMR facility. The design of improved inhibitors that can enter cells and selectively block the oncogenic state is being led by Professor Peter Fischer at the University of Nottingham, with Colin Kenyon at CSIR, Pretoria, designing deuterated analogs for enhanced activity. The result of the two year project is expected to be a set of lead molecules for development as potential therapeutic agents for breast cancer, and may yield a new approach for using nature’s own inhibitory mechanisms to block cancer-causing kinases.