Chemical Biology
The Buhrlage lab utilizes chemistry, biochemistry and cellular biology to study proteostasis in cancers. Protein homeostasis, or proteostasis, is simply defined as the processes by which cells control the concentration and conformation of the proteome. The ubiquitin system in particular is critical in controlling the concentration of proteins. Ubiquitylation is a reversible post-translational modification whose most well-known and best characterized function is tagging proteins for proteolytic degradation. However, its critical role in protein activation/inactivation, localization, signal transduction and lysosomal and autophagic degradation among other cellular processes is becoming increasingly appreciated.
Deubiquitylating enzymes (DUBs) remove ubiquitin tags in a substrate specific manner resulting in stabilization of the substrate. At present, there are approximately 95 recognized human DUB enzymes belonging to 5 distinct families. Four of the families are cysteine proteases and the fifth is comprised of zinc metalloproteases. Most DUBs have been putatively linked to physiological and/or pathophysiological functions. In particular, DUBs have garnered significant attention in the last decade as potential therapeutic targets in the field of oncology: DUBs have been shown to rescue oncogenic transcription factors including ID1 and Myc, drug resistant kinases including gefitinib resistant EGFR and ‘undruggable’ targets including Ras and other RhoGTPases from degradation in multiple cancers. Furthermore, at least 14 viral oncoproteins are reported to utilize 7 human and 4 viral DUBs in cancer development and progression.
A significant effort of the research program is focused on generating chemical tools that can be utilized to transform our understanding of normal and disease DUB biology, particularly as it pertains to protein homeostasis in cancer. Current projects include: identification of oncoprotein stabilizing DUBs, development of first-in-class inhibitors of DUBs implicated in disease, development of technologies to study the ubiquitin system, and execution of a gene family approach to identify new small molecule DUB inhibitors and scaffolds. We are also interested in developing small molecules that target protein-protein interactions in the ubiquitin system.
