Protein kinases are the second largest group of drug targets after G-protein-coupled receptors, and they account for 20-30% of the drug discovery programs of many companies. To date three protein kinase inhibitors have been approved for clinical use and a further 23 protein kinase inhibitors are known to be undergoing human clinical trials. This figure is set to increase since the protein kinases comprise the largest enzyme family with approximately 500 being encoded by the human genome. LeadDiscovery has recently featured the “Kinase Enterprise Library” which offers organizations the possibility of screening a targeted library of candidate kinase inhibitors against a wide variety of kinases. With tools like this becoming available it is now possible to rapidly identify novel lead inhibitors for kinases of interest. The challenge now is to establish the function of recently identified kinases, to establish a proof of concept for their inhibition, and to design inhibitors.

Kinases are particularly important in the etiology of cancer. Researchers at the University of Arizona have been focusing on the structure and function of oncogenic protein kinases such as Aurora 2 kinase and c-Kit. Aurora kinases are a family of mitotic serine-threonine kinases that are over-expressed in several solid tumors including pancreatic and colorectal cancer. They localize to the mitotic apparatus and regulate completion of centrosome separation, bipolar spindle assembly and chromosome segregation. Dysregulation of these kinases due to over-expression leads to defects in cytokinesis with subsequent polyploidy. The Arizona group have developed a structure-based novel small molecular inhibitor design program for several oncogenic protein kinases and have synthesized and tested these on a variety of cancer cell lines. Several small molecular inhibitors have been designed and synthesized based on existing ATP-binding site inhibitors. These are currently being evaluated in cancer cell lines, specifically pancreatic cancer cell lines.

Aurora1 or aurora2 inhibitors were designed first by demonstrating that there was significant homology between these kinases and bovine cAMP-dependent kinase (1CDK), murine cAMP-dependent kinase (1APM), and Caenorhabditis elegans twitchin kinase (1KOA) and then by building structural models of aurora1 and aurora2 using 1CDK as the template structure. Molecular dynamics and docking simulations targeting the ATP binding site of aurora2 were used to predict active-site residues that interact with reference kinase inhibitors and moieties that interact with these residues. Inhibitors with isoquinoline and quinazoline moieties were recognized by aurora2. The calculated binding energies for the docked small-molecule inhibitors were qualitatively consistent with the IC50 values generated using an in vitro kinase assay validating this in silico approach. The path is now open to dock libraries such as the Kinase Enterprise Library into the aurora2 template or to employ medicinal chemistry approaches to identify and optimize other aurora2 inhibitors.

Entry date Tuesday, April 22, 2003

Adapted from Vankayalapati et al, Mol Cancer Ther 2003 Mar;2(3):283-94- Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk