The Drug Discovery Pipeline
by Alan Saltiel
Mary Sue Coleman Director of the Life Sciences Institute
The Center for Chemical Genomics, featured in this issue, illustrates how broadly-based collaborations can leverage existing expertise across scientific areas. Chemical screening of molecular targets using robotic technologies has become an integral part of drug discovery in the pharmaceutical industry. My colleagues there have built massive chemical libraries, developed super high throughput methods for numerous biological assays, learned how to rapidly sift through active compounds to find those with the most promise and the least problems (pharmacological, pharmaceutical, toxicological and otherwise), and developed great capacity for the follow-up chemical synthesis work that is required to turn a “hit” into a new chemical entity that can be moved along the drug discovery pipeline. Indeed, the time from target identification to clinical drug candidate has shortened considerably, thanks largely to the new efficiencies of robotic screening and synthesis, and other high throughput methods.
With all the resources and attention devoted to improving the discovery process, why are drug company pipelines generally considered so poor? While there is no doubt that the problem is partly due to issues with the regulatory environment, absurd safety hurdles, cost pressures, etc, the sad truth is that the industry is looking mainly under the lamppost. They have created an amazing array of resources and technologies with which to explore the biological universe, but have instead focused narrowly on the so-called “druggable” targets. These are defined mainly by experience- the class already known to be amenable to small molecule inhibition or modulation. Thus, of the 30,000 genes and even more proteins available for investigation, only hundreds are being targeted for exploration. The pressure to develop profitable drugs -- especially drugs that act on ubiquitous, known targets -- leaves the vast majority of biological space unexplored by this powerful screening methodology.
In the Institute’s Center for Chemical Genomics, we are harnessing the power of chemical diversity, along with knowledge of molecular structure, to explore unknown biological space. We not only look at a few receptors or enzymes, but interactions among genes and proteins, or at cellular processes in the “black box” format. The targets we will explore will come from the laboratories of researchers across the university, working at every level within the organism; combining biological, chemical and structural approaches; and with and without particular disease targets in mind. Our growing chemical collections come from commercial sources but also from laboratories of faculty and collaborators, like the laboratory of David Sherman who has developed a unique collection of natural products from our planet’s oceans. Perhaps our collaborations with Shanghai Jiao Tong University will yield even more interesting compounds. Some experiments will be focused on finding small molecules that could be leads for therapies, but more likely we will be focused on developing chemical tools that advance our capacity for further discovery, and deliver new insights into spatial relationships in biology. We will take innovative approaches, such as that pioneered by new assistant professor Jason Gestwicki, who has devised a new method for inhibiting protein interactions, long considered untouchable by the pharmaceutical industry. Finally, we will marry random library screening to structure-based design, taking advantage of the resources located in our Center for Structural Biology.
Even though there is much legitimate debate about whether big pharma and their biotech partners can continue to be successful in bringing valuable drug therapies to market, we are not trying to duplicate or compete with pharmaceutical company drug development, although we might generate new ideas for drug discovery, and possibly compounds that might be the beginning of discovery projects. However, our main goal is to take a powerful methodology and put it behind the kind of open discovery present in the best academic settings. It is as though we’re using a space shuttle designed to explore nearby, known planets, and taking it on an unknown adventure to explore deep space. I am really curious and excited about what we might find by combining biology and chemistry. Whatever it is, I know that individual scientists could never find it on their own.