The Galien Forum USA 2019

"Drugging the undruggable" with novel approaches to small molecule design


In the journey of drug discovery and development, scientists are continually uncovering new pathways for treatment, often with a focus on either dialing up or dialing back the activity of a specific molecular target. Historically, this has involved identifying a protein that has a “druggable” binding pocket that can be targeted with a small molecule, or to design antibodies that bind to a specific known antigen. But some proteins aren’t so straightforward, and despite their known importance in driving disease, they continue to elude scientists—enough so that those targets are commonly called “undruggable.” And this protein-based approach still covers only a tiny fraction of the human genome; in fact, over 90% of the transcriptome comprises non-protein-encoding RNAs that play myriad roles in both normal physiology and disease pathology.

But what if we could flip this paradigm on its head and redefine what it means to be druggable? That’s the basis for a new set of approaches that scientists have been developing in an effort to expand available target space to treat elusive diseases. This panel discussion will bring in experts from academia, biotech, and industry to discuss some examples from this exciting new body of work. 

One example involves influencing the body’s natural systems for controlling protein levels, or proteostasis, so we don’t have to directly modulate target proteins. Instead, it’s become possible to degrade unwanted proteins by modulating their ubiquitination, which “tags” proteins for removal through the cellular recycling machinery—the proteasome. Targeted protein degradation has become a field os own, with methods for degrading ranging from proteolysis-targeting chimeras, or PROTACs, to molecular “glues,” both of which aim to redirect ubiquitin E3 ligases to “unnatural” substrates designated as targets of therapeutic interest. 

Another example is inspired by our improved understanding of RNA structure and its biological functions. With that understanding has come the opportunity to expand druggable space—and despite being early in the journey to a medicine, progress has been made in using small molecules in creative, nuanced ways to target specific structural elements of RNA. 

For these approaches to become promising treatments, considerable challenges lay ahead, not the least of which is proving that they can be deployed effectively and safely in human patients. The following group of experts, chaired by Pfizer President of Worldwide Research, Development and Medical, Mikael Dolsten, and representing the leading minds charting the field will address these issues in detail, with emphasis on some of the early discoveries that led to these approaches, and the different avenues worth exploring to drug the undruggable.