The Undruggable Proteome

Controlling Intracellular Protein Levels using Small Molecules

Less than 20% of the proteome has an enzymatic activity. However, current drug development efforts rely heavily on the identification of enzymatic inhibitors, thus ignoring a significant fraction of the proteome.  While RNAi technology theoretically has the potential to address this undruggable proteome, its clinical development has proven challenging.

Our lab is developing different methodologies to address this unmet need.  Specifically, we are interested in affecting different intracellular processes via the small molecule control of protein levels.  These approaches include the development of new proteasome inhibitors and small molecules that disrupt E3 Ubiquitin ligase:substrate interactions to stabilize proteins as well as new methodologies to induce selective protein degradation, such as the recruitment to targeted proteins to E3 ubiquitin ligases or appending hydrophobic tags to the surface of targeted proteins so that the intracellular protein quality control machinery will induce their degradation.  

By pharmaceutically controlling protein function via novel mechanisms that do not rely upon enzymatic inhibition, these approaches may allow one to target those proteins that are currently not ‘pharmacologically vulnerable’.

Relevant Publications:

Schneekloth JS Jr., Fonseca F, Koldobskiy M, Mandal A, Deshaies R, Sakamoto K, Crews CM
JACS 2004 126 12 3748-3754