Drug Design Caution for Biotech and Pharma Firms That Target Kinases

Drug design is never easy, and few drug candidates make it through the development pipeline and into the medicine cabinet. Side effects loom large among potential bugaboos. In the Dec. 14 online edition of the leading scientific journal Nature, a UCSF laboratory research team now reports another unintended consequence of drugs targeted against enzymes, known as kinases, within the body. Kinases drive many vital processes within cells and play a role in disease, as well. There are 500 or so kinases in the body. Cancers often overproduce certain kinases that drive tumor growth. Many drugs that target particular kinases are in development, and several already are on the market to treat cancer. Kinase inhibitors already account for billions of dollars each year in pharmaceutical sales. Peter Walter, PhD, co-chair of Biochemistry and Biophysics at UCSF, works on the unfolded protein response, or UPR, a biochemical mechanism used by cells to recover from a kind of stress that arises when they cannot keep up with the need to fold proteins into proper shape. An abnormally active UPR appears to help many tumors survive and keep up with the protein processing demands that arise from rapid cell growth. Walter’s research team now reports that a kinase serving as the linchpin in this biochemical mechanism may be affected by kinase inhibitors in ways that may lessen the cancer-fighting potential of some of these drugs. Walter and UCSF colleagues Robert Stroud, PhD, and Kevan Shokat, PhD, led a tour-de-force effort to define the unusual functional structure of an enzyme called Ire1, which is the linchpin of the UPR. Ire1 actually is two enzymes in one. It combines a kinase with another enzyme activity, called RNase. The RNase activity of Ire1, aided by its own kinase, generates a pro-survival signal within the cell. As part of the studies, the researchers probed the effects of different kinase inhibitors on Ire1. Oddly, the kinase inhibitors can supercharge the RNase function of Ire1, making cells more fit for survival, the researchers concluded. The kinase inhibitors tested included sunitinib, an already marketed anti-cancer drug. “Cancer cells could benefit from activation of Ire1, even though a drug is designed to kill the cells,” Walter says. “We found that kinase inhibitors – including sunitinib – act as potent activators of the Ire1 RNase,” the researchers reported in Nature. “Because Ire1 provides cytoprotective function from which cancer cells may benefit, it may be of therapeutic value to separate the intended function of the kinase inhibitors towards the targets for which they were designed from the activation of Ire1.”

 

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