TPD & Induced Proximity 101 Bootcamp Day
Monday, October 28 2024
7:00 am Check-in & Morning Coffee
8:15 am Chair’s Opening Remarks
Introducing the Fundamental Principles Underpinning Targeted Protein Degradation & Induced Proximity to Jump-Start Your Degrader Program
9:00 am Harnessing Protein Degradation to Drug the Undruggable: The History & Promise of Targeted Protein Degradation
Synopsis
- The field of targeted protein degradation has rapidly expanded to offer the potential to drug targets that were previously considered undruggable
- PROTACs, MoDEs, and molecular glues have led the way into clinical trials and have shown promise for durable, effective therapeutics in cancer and other indications
- Multiple new targeted protein degradation modalities have been developed in the preclinical space that may allow targeting signaling pathways, cell types and tissues that were previously thought to be difficult to drug
9:30 am Structure & Regulation of the Proteasome
Synopsis
- The proteasome degrades ubiquitinated proteins by unfolding them and translocating them into a proteolytic chamber
- The proteasome is regulated by numerous cofactors, among them substrate delivery factors, inhibitors, deubiquitinating enzymes, protein kinases, ubiquitin ligases, and assembly chaperones
- Whether a ubiquitinated protein is a good proteasome substrate depends on multiple features, a major one being the presence of an “initiation element” that is is critical for effective unfolding
10:00 am Morning Break & Networking
Meet the E3 Ligase Family: Understanding this Protein’s Role in Protein Degradation & Development into Therapeutics
11:30 am Novel E3 Ligase-Based Targeted Protein Degradation: Potential Applications Within & Beyond Cancer Therapy
Synopsis
- Somatic mutation of some E3 ligases create novel E3 ligase that are not exist in normal tissues
- Targeted protein degradation using the mutated E3 ligases are very specific and only happen with the presence of the mutated E3 ligase
- Novel E3-based TPD and potential applications are discussed with an example
12:00 pm Gluing the Pieces Together, to Break it All Down: Harnessing Novel E3 Ligases for Molecular Glue Degraders
Synopsis
- The TPD field currently lacks rational chemical design principles for converting protein-targeting ligands into molecular glues
- Using known protein binders, we sought to identify transposable motifs which would convert these ligands into protein degraders
- RNF126, a previously unliganded RING E3 ligase, was determined to be an amenable ligase mediating a multitude of neo-substrate recognition events, leading to the discovery that it could be harnessed in a protein complex and act as an effective ubiquitinating and degrading chaperone
12:30 pm Networking Lunch Break
1:30 pm Roundtable Discussion: Expanding E3 ligase Platforms for Targeted Protein Degradation
Synopsis
- Current state of the art, selection of Next-Gen E3 ligases and winning screening strategies, e.g. Rational design Hit ID, phenotypic function 1st, computational AI-ML
- Accelerated workflows for binder to degrader conversion
- Tissue- specific and tissue restricted TPD : has this underdelivered and what are the main obstacles?
- Expanding molecular glue potential of E3 ligands
2:00 pm Discovery & Development of Small-Molecule Glue Degraders of KRAS G12D as the First-in-Class Anticancer Drugs
Synopsis
- Cancer cell-based drug screening identified hit compounds that abide Lipinski rule and degrade active GTP KRAS G12D protein in KRAS G12D mutated cancer cells
- High-throughput technologies revealed a novel E3 ligase and mechanism of drug action in which degraders bind the E3 ligase and KRAS G12D and induce the KRAS degradation
- Protein structure-guided and AI-powered drug design speeded up hit to lead optimization for identification of preclinical candidates as the first-in-class anticancer drugs
2:15 pm End of TPD 101 Bootcamp Day 2024
Unleashing the Full Potential of Protein Degradation Machinery with New Applications
2:30 pm Afternoon Break & Networking
3:00 pm A Landscape Review of TPD-Based Drug Development
Synopsis
- An overview of the drug & trial landscape
- A recap of the developments in 2024 so far
- Insights into novel degraders & a look to the future
3:20 pm Molecular Glues for Target Protein Degradation
Synopsis
- Emerging themes in molecular glue degrader mechanisms
- How molecular glue degraders are advancing as therapeutics
- Moving from serendipitous discovery to rationale design
3:50 pm ASGPR vs M6PR: Common & Orthogonal Applications for Extracellular Protein Degradation
Synopsis
- Review of two endocytotic cell surface receptors, ASGPR and M6PR, and their uses for degrading soluble circulating and membrane proteins
- Novel proprietary ligands for ASGPR and M6PR as backbones for ATAC (ASGPR Targeting Chimeras) and MTAC (M6PR Targeting Chimeras) degraders
- In vitro and in vivo protein degradation studies comparing ATACs vs MTACs and therapeutic implications