Non-ATP Kinase Inhibitors
"As binding of ATP is essential for kinase activity, the discovery of small molecule ligands that compete for the ATP binding site has been the main source for new kinase inhibitors. However, due to the relative structural conservation of ATP binding sites for more than 500 protein kinases in the human genome, molecules that compete with ATP binding often cross-react with many different kinases," explained Alex Kiselyov, Ph.D., executive vp of R&D at ChemDiv (www.chemdiv.com). On the flip side, kinase inhibitors displaying "dual" activity against multiple kinases are of particular interest in oncology due to the synergy potential.
ChemDiv has launched several programs that have yielded non-ATP-competitive kinase antagonists. They have also developed a strategy for identification of non-ATP competitive kinase inhibitors based on the Pocketome algorithm developed by Ruben Abagyan at MolSoft (www.molsoft.com). A focused compound library called the Focused Diversity Set (FDS) has been assembled.
FDS includes a selection of 5,000 fully characterized, chemically distinct compounds annotated against orthogonal biological targets, i.e., targets from different families, pathways, and cellular processes. The company has validated the FDS approach in the identification of novel dual AT1/ETA antagonists, PI3KCA-specific inhibitors, EGFR/KDR, and tubulin modulators for oncological indications, according to Dr. Kiselyov. ChemDiv has also been able to develop non-ATP competitive inhibitors of bcr-Abl kinase that are based on a non-ATP competitive mechanism of enzyme inhibition.
Enrique Michelotti, group leader, medicinal chemistry at Locus Pharmaceuticals (www.locuspharma.com), explained that Locus’ approach to kinase inhibitors is a fragment-based strategy that enables the quick identification of biologically relevant binding sites and novel small molecule drug candidates. The company is focusing its attention on developing therapeutics for the treatment of arthritis/inflammation, cancer, and HIV/AIDS.
Dr. Michelotti discussed and presented results on several of the company’s lead kinase inhibitor compounds. These compounds belong to a new class of p38 inhibitors that is based on allosteric inhibition of a conserved non-ATP kinase site as opposed to the more traditional ATP site-dependent classes.
This new breed of compounds confers high selectivity, potency, and improved safety characteristics. Cell assays demonstrated that the mechanism of action was due to complete inhibition of the p38 specific activation pathway thus validating p38 as the unique intervention point for the LOC allosteric inhibitors, Dr. Michelotti said.
In a seminar on finding hits for kinases, Michael Charlton, Ph.D., group leader of computational chemistry at Evotec (www.evotec.com), explained that his company uses a cheminformatics approach to find kinase inhibitors. Evotec has built a database of over three million compounds derived from various suppliers and categorized them into drug-, lead- and non-druglike compounds based on predetermined criteria and queries.
The company has identified a new way of describing molecules and used a technique known as Kohonen mapping to add several thousand compound candidates to its screening collection. The application of this virtual screening approach to finding kinase inhibitors has been validated by results that demonstrated over 40-fold enrichment compared to a random screening approach.