SC11: Targeted Protein Degradation Using PROTACS and Molecular Glues
MONDAY, APRIL 8, 6:00 – 9:00 PM (Dinner Provided)

Targeted protein degradation using molecular glues and bifunctional small molecules known as proteolysis-targeting chimeric molecules (PROTACs) are emerging as a useful tool for drug discovery, and as a new therapeutic modality for chasing previously “undruggable” targets. This course will cover the basic understanding of what these entities are, how they work and how they can be applied to target and degrade specific proteins of interest. Case studies drawn from the work that the instructors have done in their labs will also be presented.

Topics to be covered:

• Pros and cons of using PROTACs versus Molecular Glues
• PROTACs and molecular glues, do we use them to induce protein degradation only?
• Which binding site on E3 ligase should be targeted by PROTACS/Glues for the efficient substrate recruitment?
• Molecular events required for PROTAC mediated degradation (ternary complex, availability of lysines, orientation of E3s, and more)
• New screening technologies available to discover PROTAC and molecular glues for E3 ligases

Instructors:

Lara Gechijian, PhD, Scientist/Project Lead, Jnana Therapeutics; Former Graduate Student, Laboratory of Drs. James Bradner/Nathanael Gray, Harvard Medical School

During her undergraduate years at Wellesley College, Lara worked as a research assistant in the lab of Matthew Meyerson (Broad Institute of Harvard and MIT) where she conducted research on the characterization of the potency, activity, and functional effects of a novel cytotoxic agent. Lara completed a PhD candidate in Biomedical and Biological Sciences and Therapeutics at Harvard Medical School.  She conducted her graduate research in the labs of Dr. Jay Bradner and Dr. Nathanael Gray where she focused on targeted degradation as an approach to developing novel epigenetic cancer therapeutics. Lara is currently a biochemist at Jnana Therapeutics, a biotech company dedicated to launching solute carrier transporters to the forefront of medicine.

Eric Fischer, PhD, Assistant Professor, Cancer Biology, Dana-Farber Cancer Institute/Harvard Medical School

After studying biology at the University of Basel in Switzerland, Eric Fischer obtained his PhD at the Friedrich Miescher Institute for Biomedical Research were he conducted pioneering work on the structure, function and mechanism of action of thalidomide and its efficacy target Cereblon. After his PhD he moved to the Dana-Farber Cancer Institute to start his lab in the vibrant chemical biology community in Boston. He is also an Assistant Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School. Dr. Fischer has been recognized for his pioneering work on the structure of cereblon and the mechanism of action of thalidomide and has significantly contributed to our understanding of small molecule mediated protein degradation. His lab studies the structure and function of ubiquitin E3 ligases and translates these insights into the development of novel therapeutic strategies.

Alexander Statsyuk, PhD, Assistant Professor, Department of Pharmacological and Pharmaceutical Sciences, University of Houston

Alexander Statsyuk is an assistant professor at the University of Houston College of Pharmacy. He obtained his PhD. degree at the University of Chicago in 2006, where he synthesized natural product Bistramide A and established its mode of action in cells. He then completed his postdoctoral work at UCSF, where he was working on the development of chemical cross-linkers to identify upstream kinases of protein phosphorylation sites. Since 2010 he has been running his independent research program aimed at discovering drug leads targeting degradation pathways such as ubiquitin proteasome system and autophagy. He is an author of 32 manuscripts, he filed 10 patent applications, and he is a recipient of Pew Scholar Award. Some of the technologies that he and his group have developed and patented include covalent fragments, novel probes UbFluor to conduct HTS screens to discover E3 ligase inhibitors and hijackers, and E3-Substrate crosslinkers useful to study E3-Substrate interactions in vitro and to validate E3-Substrate hijackers in vitro.