SC9: TARGETED PROTEIN DEGRADATION USING PROTACs, MOLECULAR GLUES AND MORE

WEDNESDAY, SEPTEMBER 18 | 7:00 - 9:30 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 Discussed:

  • Pros and cons of using PROTACs versus Molecular Glues
  • PROTACs and molecular glues, do we use them to induce protein degradation only?
  • 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
  • Applying enzymology concepts to the optimization of targeted protein degraders
  • Protein degradation beyond bi-functional degraders
  • Exploring use of PROTACs and other protein degraders for oncology treatments
  • Pursuing previously undruggable protein targets
  • Issues surrounding PK/PD, biotransformation and in vivo delivery

Instructors:

Statsyuk_AlexanderAlexander 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.

Robinson_JamesJames Robinson, PhD, Team Leader, Discovery Sciences, AstraZeneca

James studied for his PhD at University College London investigating mechanisms of GPCR signalling and regulation. He then moved to The Scripps Research Institute to undertake a postdoc focussed on mechanistic pharmacology of the Orexin-1 Receptor. He joined AstraZeneca in early 2015, originally in the assay development group, where he developed a broad range of assays for neuroscience, oncology and immuno-oncology projects. In early 2019 he moved into AstraZeneca’s Mechanistic Biology and Profiling department. There he leads a team of scientists with the goal of optimising drug candidates through quantitative mechanistic characterisation and understanding how this modulates cellular systems in cancer.

Fisher_StewartStewart Fisher, PhD, CSO, C4 Therapeutics

Dr. Fisher is the Chief Scientific Officer at C4 Therapeutics, a new biotechnology company focused on the selective recruitment of targets to E3 ligases for ubiquitination and degradation by the ubitiquin/proteasome system where he is responsible for strategic delivery of the project portfolio and collaboration management. Prior to joining C4, Dr. Fisher was the Director of Enzymology and Quantitative Biochemistry in the Center for the Development of Therapeutics at the Broad Institute. His group focused on the mechanistic analysis and quantitative assessment of protein:ligand interactions required for therapeutic discovery. Prior to joining the Broad Institute, Dr. Fisher spent 15 years at AstraZeneca in the Infectious Diseases Innovative Medicines Unit, where he led numerous antibacterial programs that progressed through Phase I clinical trials and was the Executive Director, Biological Sciences. His department supported the entire drug discovery project portfolio, from target validation to pharmacodynamics modeling in support of Phase III candidates. In addition, Dr. Fisher spent 2 years at Hoffmann LaRoche leading drug discovery programs in Metabolic Diseases. Dr. Fisher received his BA in Chemistry at the University of Vermont and PhD in Chemistry at Caltech and was a National Institutes of Health Post-Doctoral Fellow at the Harvard Medical School with Professor Christopher T. Walsh.

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