Whether you are a bow hunter studying the forest for signs that this is the perfect location to set up your stand to await the appearance of a trophy buck, or a mushroomer looking for evidence of the right kind of decaying tree to alert you that coveted morels are nearby, or a lawyer pouring through dusty law books seeking that perfect precedent to win your case, successful hunters all share the trait of having an intimate, almost intuitive knowledge of their prey. Drug hunters are no different. They strive to understand the underlying physiology and biochemistry that ultimately manifest as symptoms of a particular disease, and seek targets that they can use their knowledge and experience to exploit for developing new therapies.
There have been several articles in recent months reporting on efforts to expand the available armamentarium we can deploy against diseases. The Pew Trust initiates a “roadmap” aiming to break barriers to finding new antibiotics; a British group reports a tabulation of new genetic targets for treating cancer. I have been particularly interested in a couple of articles by Robert Plenge. On his blog page he wrote in April about connecting known human biology with target selection to identify the most useful path toward developing a therapeutic. That post was followed up this month with a publication in Science Translation Medicine where he expanded on those ideas.
As pointed out by Plenge, the history of pharmaceutical drug discovery has been one where correlation leads to a lot of investment in screening. While in the field of infectious disease, enzyme targets yield cures, in most other human disease, drug targets don’t always line up with a true cure. Even supposed cures (for example, insulin for diabetes) account for a symptom (depletion of insulin) without actually addressing the underlying cause (e.g. development of insulin insensitivity in Type II diabetes). In his recent article, Plenge outlines some examples where a genetic understanding of the disease has led to more accurately targeted therapeutics. But I am uncertain, as in this recent report mapping new genes for autism, that expanding gene targets from 65 to 2,500 makes development of effective therapeutics more likely.
I cannot count the number of conversations I have had during my big pharma career where a drug target was lauded for its “druggability.” Certainly potent pharmacophores can be found to modulate GPCRs, tyrosine kinases, transporters and other similar cellular targets. But, for all the pharmacological effectiveness, translation to clinical utility has often been modest at best. Part of the problem is that nature has evolved numerous genetically similar signal transduction systems, making selectivity very difficult to achieve. This in turn results in undesirable off-target side effects. But certainly another dimension of the problem is that the druggable targets are actually downstream of the biochemical perturbation that is resulting in the disease.
The recent news that a drug targeting a new mechanism to treat Alzheimer’s disease (tau protein) failed in Phase 3 emphasizes the point that Plenge makes in his article: To advance development of effective therapeutics, we have to focus directly on causation, not on symptomatic sequelae. The challenge for drug discoverers is not a lack of potential targets but a willingness to expand the definition of what is druggable. Exploring new classes of drug targets will certainly require inventiveness in assay development. Perhaps assays focused on expression of specific GPCR targets are ultimately less useful than those that judiciously combine phenotype and target, where an investment in understanding the connection between the biochemical phenotype and consequent physiological perturbation yields new, effective therapeutics. Fifteen years ago, when Aurora and the CF Foundation undertook the development of drugs targeting the known genetic cause of cystic fibrosis, the CFTR, many in the field were skeptical that such a drug could be effective since the target was not a conventional druggable protein. Yet now Vertex has two drugs on the market specifically modulating CFTR function making profound changes on the lives of patients. There are other examples of new targets being explored in early stages of drug discovery. Perhaps we finally are at a stage where the investment in understanding the true cause of a disease won’t frighten drug hunters away from the novelty of the target. The only result of this new era of drug hunting will be improving the health of millions of patients.