Seminar
Tuesday, November 27, 2018 - 12:00am
Graduate Student Brianna Dalesandro will present
"PROTAC-Induced Protein Degradation: A New Approach in Drug Discovery"
on November 27, 2018 at 4:10pm in Neville Hall, room 3
Induced protein degradation is a rising advancement in the area of drug discovery. Current approaches feature small molecule inhibitors or genetic knockdown strategies to target proteins associated with various diseases and cancers1. Although these methods have seen some success clinically, there are several shortcomings associated with such techniques, including cell permeability, metabolic stability, and lack of specificity. Directing focus towards protein knockdown strategies, a nontraditional approach was developed to degrade target proteins by means of a proteolysis targeting chimera (PROTAC). This heterobifunctional molecule hijacks the ubiquitin proteasome system (UPS) to specifically and catalytically degrade proteins that have known association to cancers and various diseases2. With the initial PROTAC developed in 2001, there has been substantial progression made towards optimizing PROTAC technology at the therapeutic level. Current PROTACs exhibit that a transition from peptide to small molecule binding moieties increases cellular permeability yielding successful in vivo application3. Furthering the PROTAC’s broadened application, a variety of E3 ligases can be targeted utilizing known ligase substrates to effectively decrease desired protein concentration4. Finally, a recent advancement has shown that immune cells employ an endogenous PROTAC approach by means of an E3 ligase, TRIM21, to combat invading pathogens5. References 1. Toure, M. & Crews, C. M. Small-Molecule PROTACS: New Approaches to Protein Degradation. Angew. Chem. Int. Ed Engl. 55, 1966–1973 (2016). 2. Sakamoto, K. M. et al. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc. Natl. Acad. Sci. U. S. A. 98, 8554–8559 (2001). 3. Winter, G. E. et al. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348, 1376–1381 (2015). 4. Bondeson, D. P. et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat. Chem. Biol. 11, 611 (2015). 5. Clift, D. et al. A Method for the Acute and Rapid Degradation of Endogenous Proteins. Cell 171, 1692-1706.e18 (2017).