In the early 1980s, scientists started to make connections between kinases, general cell proliferation, and promotion of cancer growth. One of the early reviews on the subject appeared in 1982. This paper (Weinstein, I.B., et al., “Results and speculations related to recent studies on mechanisms of tumor promotion”) made the first connections between kinase activity and growth of tumor cells. Over the course of the next few years, scientific knowledge about kinases continued to evolve, prompting pharmaceutical companies to invest research dollars on kinases as potential targets for pharmacological intervention.
Two decades after the chatter about kinases began, research efforts culminated in the approval of Gleevec®. Gleevec, also known as imanitib tosylate, proved to be a spectacular success—addressing an important unmet medical need and bringing Novartis(www.novartis.com) more than $1 billion a year in revenue.
Gleevec inhibits activity of a nonreceptor tyrosine kinase, ABL, which drives proliferation of cells in chronic myelogenous leukemia. These cells contain the so-called Philadelphia chromosome (Ph) with t(9;22) translocation where a part of the abl gene is fused to a part of the bcr gene, resulting in expression of the hybrid BRC/ABL protein with constitutive kinase activity.
Treatment with Gleevec not only suppresses the kinase activity of the fusion protein, but also inhibits proliferation of the cells. In some cases, Gleevec even eliminates all cells containing the Philadelphia chromosome from patient’s blood and bone marrow, leading to apparent cures of the disease.
Based on the success of Gleevec, what are the prospects for other kinase inhibitors? From the data generated by the sequencing of the human genome we know that there are no less than 500 kinases. More then half are now cloned, expressed, and available to evaluate activity of potential inhibitors. Currently there are only seven kinase inhibitors that are approved drugs on the market.
Three of these inhibitors were designed to target BCR/ABL, two others at epidermal growth factor receptor 1 (EGFR-1), one at RAF, and one at the kinase insert domain receptor (KDR) or the vascular endothelial growth factor receptor 2 (VEGFR-2). Thus far, four kinase targets have proved to be useful for therapeutic interventions. Why so few? Are researchers doing something wrong and, if so, how can we fix it?
We have to keep in mind that the drug discovery and development process is extremely difficult due to our poor understanding of biology of the disease and biology of the host (i.e., Homo sapiens). We are making steady progress, but there is still a long way to go. The seven marketed kinase inhibitors cited in this article, in theory, target four kinases in total. In reality, these inhibitors actually target at least 17 kinases, but only the four are thought to contribute to therapeutic effect. Considering this, how targeted should a targeted therapy be? Should a compound targeting three kinases (e.g., Gleevec) be in the category of targeted therapies?