Everyone knows that off-targets are the bane of a drug developers existence, but surprisingly little has been done to address the problem. Nature’s paper from the time machine, “Reducing safety-related drug attrition: the use of in vitro pharmacological profiling,” describes the systems and strategies evolved by big pharma (specifically AstraZeneca, GlaxoSmithKline, Novartis and Pfizer) to approach this challenge.
The article is especially interesting because of the paucity of reliable information in this area. As the authors point out, only hERG blockade is required by the FDA, but an enormous diversity of off-targets are responsible for drug failure after drug failure. So how any given investigator or company tackles this issue is up to them, with few industry standards: it’s the Wild West.
That’s what makes this particular article so interesting–and why we’re reviving it. Here we get a window into how the best and brightest, with unlimited resources, attacked this problem. Not surprisingly, they all engaged high-throughput screening of their candidate drugs against a large panel of receptors, mostly those perceived as “bad.” The reasoning behind the receptor roster in such panels was obviously critical to success and most of the article surveys this reasoning.However, a common red flag was promiscuity, a drug that binds a lot of receptors, regardless of their identity, is untameable.
The challenge faced by all such in vitro methods, even those as high dimensional as described in this article, are the inevitable surprises when the drug development moves to in vivo. As clever as the off-target profiling described here is, new methods are needed to connect the results to the in vivo outcomes. GeneCentrix believes that the frontier in meeting this challenge is tissue specificity and has come up with a user-friendly software product and consulting service to address the problem, including innovative new tissue-specific tools.