Allosteric Protein Kinase Modulators via Disulfide Trapping
Initial Award Abstract
Protein kinases are enzymes that are essential for normal cellular functions; when unregulated, however, kinases also play central roles in cancer. Many currently-used cancer therapeutics are kinase inhibitors. The development of kinase-targeted drugs is usually founded upon basic biochemical and cell biology studies focused on understanding the role of specific kinases in biology. To reach this understanding, methods that allow one to selectively inhibit or activate a single kinase and observe the resulting cellular effects in real time are ideal. Most current methods to do this, however, are either not selective (i.e., they affect several kinases at once) or do not allow fine control over kinase activity in time or in degree.
I propose to develop novel molecules that modulate the activity of protein kinase C iota (PKC-iota) by binding to this protein in a novel way. The strategy I will employ involves the use of a drug discovery technology developed at Sunesis pharmaceuticals called disulfide-trapping (or Tethering), which has been successful with several protein targets. Human non-small-cell lung cancer cells have high levels of activated PKC-iota and this feature is correlated with abnormal growth and migration of these cells, but the precise mechanism by which this occurs is not completely understood. Therefore, the long term application of the basic research I propose is to develop a cellular model of the above diseases in which PKC-iota can be selectively turned on or turned off at will (simulating the cancerous state in the former case and simulating the actions of a drug in the latter case) and subsequent cellular events can be monitored over time. Uncovering the pathway through which PKC-iota exerts its lung cancer-promoting effects may validate this enzyme or other enzymes in the pathway as targets for future drug discovery efforts. |