Special Seminar - Dr. Darren Derksen

Title:

Using Natural Product Structure-Activity Relationship (SAR) Studies and Proteolysis-Targeting Chimeras (PROTACs) to Target Protein Function

Abstract:

Targeting protein function or protein-protein interactions is a central theme in medicinal chemistry and drug design.  Modulation of TRP channels has been shown to impact pain signaling in animal models with examples now in clinical trials.  This presentation will showcase recent work in our group exploring structure-activity relationships on natural products that interact with TRP channels, particularly TRPM8.  In the course of this study, we have developed photo-rearrangement chemistry as a route to desired natural product targets.

The traditional approach of developing protein inhibitors has been less successful when targeting proteins that lack a clear active site and are non-enzymatic.  Recent work from pharmaceutical companies and research groups around the world, including the Derksen group, have demonstrated that PROTACs offer a potential solution through degradation of challenging protein targets.  By synthesizing heterobifunctional PROTAC molecules capable of inducing close proximity of target proteins and the cellular ubiquitination machinery, we have shown that an important anti-apoptotic protein MCL1, can successfully be degraded.  Our recent efforts in the design and synthesis of PROTACs capable of chemically inducing degradation of MCL1 will be described.