Degrading Proteins for a Therapeutic Response Lecture Notes PDF
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Uploaded by EliteAmbiguity1280
University of California, Irvine
2024
Prof. Trader
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Summary
These lecture notes discuss protein degradation and its role in therapeutic responses. It covers various pathways and inhibitors involved and details mechanisms associated with protein degradation. The lecture notes feature various diagrams and figures, highlighting important concepts.
Full Transcript
Degrading Proteins for a Therapeutic Response Winter 2024 Prof. Trader PharmSci 177/277 The Central Dogma https://www.scienceholic.org/post/the-exception-to-the-central-dogma Nature Reviews Drug Discovery volume 1, pages727–730 (2002) Nature Reviews Drug Disc...
Degrading Proteins for a Therapeutic Response Winter 2024 Prof. Trader PharmSci 177/277 The Central Dogma https://www.scienceholic.org/post/the-exception-to-the-central-dogma Nature Reviews Drug Discovery volume 1, pages727–730 (2002) Nature Reviews Drug Discovery volume 1, pages727–730 (2002) Why Inhibitors Can Fail What other cellular processes can we drug? Protein Degradation Pathways Proteasome (UPS) Autophagy 30S Proteasome Active Sites Signal for Proteasome Degradation- Ubiquitin (Ub) Proteasome Inhibitors- Blood Cancer Treatments MG132 Inhibition- Aldehyde O O H N H O N N H H O O Peptide Vinyl Sulfone Peptide Epoxy Ketone Pathways that require proteasome activity Have proteasome degrade a desired protein for a therapeutic response? E3 Ligands Most common E3 Ligases to Target VHL CRBN CRBN Ligands Examples of PROTAC chemical structures. Chemical structures of three BRD4 degraders: (left to right) CRBN-based dBET6, VHL-based MZ1 and IAP-based SNIPER(BRD)1. Example of a ternary complex. X-ray crystal structure of PROTAC 1 (green) bound in a ternary complex with the bromodomain of its protein target SMARCA2 (pale orange) and the E3 ligase VHL (teal). How do you determine protein degradation? Western Blot Degradation of BRD4 observed by western blotting in HEK293 cells treated with the active l-CIDE but not the inactive d-CIDE. Blots are representative of five independent experiments. Case Study: BRD4 Degradation “BRD4 is a transcriptional and epigenetic regulator that plays a pivotal role during embryogenesis and cancer development.” Concentration Dependent Time Dependent Controls: Showing that your molecule does what you hope it does Targeting to Diseased Cells Light Activated PROTAC Antibody PROTACs Covalent PROTACs What are these limitation? Future
