Protein kinase inhibitors are very popular, and drug companies are likely to develop more of them as functional genomic data lead to increased kinase discovery.
Trends come and go in nearly every industry. And the drug industry is no exception. But, what does it take for a drug (or a class of drugs) to become a mainstay in an industry where the only constant seems to be change? Well, intuitively, the drug’s target must be one that is vitally important to a disease process and does not fade away from the public health need like the colors in a poorly-made, tie-dye shirt in a bleach-filled washer. There have been a few examples of major drug classes that have stood the test of time, namely antibiotics (which categorically expand to anti-fungals, anti-bacterials, and anti-virals) and antidepressants. Now, there seems to be a new one: protein kinase inhibitors.
When the human genome sequence was published earlier this decade, 518 out of the thousands of hypothetical proteins predicted from the sequence were protein kinases. And what’s more, “[protein] kinases account for 25% to 30% of all targets screened in the pharmaceutical industry today,” says Francois Degorce, head of HTRF marketing at Cisbio, Bagnols, France. In fact, he says, protein kinases are screened more so than other enzymes, such as proteases, for example.
There is much interest in protein kinase inhibitors in oncology, as potential cancer drugs. “For over ten years now, we, the pharmaceutical industry, recognized that many [protein] kinases are druggable, so that we can attack these targets more or less selectively using small-molecule inhibitors,” says Robert T. Abraham, PhD, vice president, Oncology Discovery Research, Wyeth Research, Pearl River, N.Y. “Actually, of the myriad proteins that are in cells, only a relatively small subpopulation of them (that would include [protein] kinases, GPCRs, etc.) have actually been shown to be druggable by small molecules.”
Protein kinases are very druggable, as evidenced by the very large number of inhibitors being developed every year. But, as more and more protein kinases are discovered as potential targets, will we see an increase in what appears to be the newest trend in drug discovery and development?
Not just a trend
Many pharmaceutical companies have chosen protein kinases as drug targets because they go hand-in-hand with cancer and can be targeted by small-molecule chemistry. Consequently, there are heaps and heaps of scientific papers that prove the link between mutated protein kinases and cancer.
One researcher studying protein kinases is Peter Ho, MD, PhD, senior vice president of the GlaxoSmithKline (GSK) Oncology Center of Excellence in Drug Discovery, Philadelphia, Pa. For oncology research at GSK, protein kinase inhibitors make up more than 50% of the drug discovery effort. GSK focuses on protein kinases that are involved in signal transduction as it relates to oncogenesis. And more and more protein kinases that play a role in this process emerge every day. “One of the things we are doing is profiling which of the emerging protein kinases are important in oncogenesis and those that appear more important are being prioritized as targets for us,” says Ho.About the recent dramatic increase in protein kinase inhibitor development, Ho had this to say. “Sure, we have all seen that. But as a target, [protein] kinases are still relatively new in the sense that it was not that long ago—let’s say the early 90s—that there were still questions raised about whether [protein] kinases represented a good target.”
So, how many protein kinases does a typical protein kinase inhibitor inhibit? Protein kinases have a common mechanism of action (M.O.A.): they bind ATP and then phosphorylate themselves and/or other proteins to aid in the transmission of a “signal” of information, typically from the plasma membrane to the nucleus of the cell. Says Wendell Wierenga, PhD, executive vice president, Research & Development, Ambit Biosciences, San Diego, Calif.: “[Protein] kinase inhibitors tend to work by competing with ATP for binding in the catalytic site of the [protein] kinase. Because of this common M.O.A., it is very difficult to find compounds that would be specific for a particular [protein] kinase.”
However, Ho explains that researchers have learned from preclinical and clinical experience that, although there is conservation in the ATP-binding pocket, there is still enough variability for specific inhibitors to be developed against the different protein kinases. This specificity is important for designing inhibitors that target only one protein kinase.
There are some companies focused exclusively on oncology that have made it a strategic imperative to be amongst the leaders in kinase drug discovery and development. That is what Exelixis, South San Francisco, Calif., has done. Exelixis president of R&D Michael Morrissey, PhD, gives two reasons for this imperative. “First, the protein kinases themselves and their pathways are so integral to the biology of cancer that targeting them makes a major impact relative on the disease’s pathobiology. And second, all of the drug discovery and development technologies seem to be built for studying [protein] kinases.” He expounds on the second reason by saying that [protein] kinases are easy to screen, crystallize, and solve structures for, perform pharmacodynamic studies on, and so on.
The saga continues
And now back to specificity of [protein] kinases. “There was a lot of controversy going back to Gleevec—when it was discovered in the 1980s at Ciba-Geigy and Novartis—debating whether or not you needed to have high specificity for a single [protein] kinase to have good activity and good tolerability in the clinical setting,” says Morrissey. “So our view early on at Exelixis was that, for given classes of [protein] kinases —and more importantly, different disease states like cancer—a multi-targeted approach would probably be more effective, therapeutically, than going after a single given [protein] kinase.”
Morrissey explains that this multi-target approach to drug discovery is especially important in the area of receptor tyrosine kinases (RTK) because tumor cells have a large number of redundant RTKs that turn the proliferative pathway on or off. “I think we were one of the first companies to have a strong program focused on the RTK called Met. We now have a compound at mid-Phase 2 and another maybe a half step behind it.” Over the last seven years, Exelixis has been busy building a platform around [protein] kinase drug discovery and development and now has 14 compounds in the clinic.
And in other protein kinase inhibitor news: Earlier this year, Wyeth had the first mTOR inhibitor approved for the treatment of advanced renal cancer. The inhibitor called TORISEL blocks the activity of mTOR—a protein kinase that resides in the PI3K signaling network. “We here at oncology discovery have been investing a lot of effort into mTOR as a target for a couple of reasons,” says Abraham. “First, we have clinical validation with TORISEL that if we attack this network appropriately, we can have a positive impact on cancer. Second, there is a massive body of compelling evidence that the hyperactivation of the PI3K network is a common feature of many human cancers, including some of the most difficult-to-treat cancers out there from breast to lung to colon to melanoma to glioblastoma.”
Because of their previous success in designing effective protein kinase inhibitors, many drug researchers feel confident that they can generate an inhibitor against any kinase. However, they also know that there are only a finite number of protein kinases in the genome to mine. So eventually they will have mined the entire human kinome. Until then, drug discovery and development in the protein kinase inhibitor area will undoubtedly remain fruitful, not just another soon-to-die trend.
This article was published in Drug Discovery & Development magazine: Vol. 10, No. 12, December, 2007, pp. 18-22.
Filed Under: Drug Discovery