Pre-Conference Workshop Day
Tuesday May 10, 2022
Leveraging the Structure-Based Design of Proximity Inducing Molecules
9:30 – 12:00
Key Discussion Topics include:
- Functional genomics and mechanism discovery
- computational modeling of polymers
- cryo-EM and biophysical characterization
- Does BCL6 polymerize in cells without BI-3802?- Is it mimicking some natural process induced by PTM or metabolite?
- How to identify / screen for another small molecule polymerizer?
- Would polymerization be a mode to modulate/control the level of protein downstream signaling or whatever type of gain of function
- What would be the gain of function - increased local concentration - inducing secondary structure of chromatin?
- What are the advantages of trimodal mechanism for BI-3802: inhibitor - blocks BCOR-BCL6 interaction. polymerizer- sequestration from DNA degrader – proteasomal degradation
- How could computational methods aid design and discovery of small molecule polymerizers?
- Use of BTB domain as polymerization switch What’s the advantages for oligomerization vs. dimerization?
- How to identify proteins with gain-on function through polymerization? Where BTB switch can be employed?
- Could induced polymerization result in increased catalytic activity of other enzymes beyond E3 ligases?
Fischer Lab, Group Leader at the Center for Protein Degradation
Group Leader, Cancer Program, Ebert Lab, Broad Institute Senior Staff Scientist
Dana-Farber Cancer Institute
Shourya S. Roy Burman
Dr. Eric Fischer’s lab Dana-Farber Cancer Institute & Harvard Medical School
Postdoctoral Associate - Ebert lab
Broad Institute of MIT & Harvard
12:00 - 13:00
Better Understanding Emerging Extracellular Antigen-based Induced Proximity Therapeutics
13:00 – 15:30
- Emerging methods to target cell-surface antigens and proteins towards degradation
- What are the benefits of leveraging extracellular induced proximity between proteins?
- What are characteristics of the current antibody conjugate formats?
- How do we improve the initial tool/probes towards a therapeutic index?
- Can we develop a rule-set for designing antibody-based proximity drugs?
- Discuss the pros/cons of antibodies vs. small molecule-based antigen recognition
Examples of formats to be discussed:
A) AbTACs: Antibody-Based PROTACs for the Degradation of the Cell-Surface
Immune Checkpoint Protein PD-L1.
B) Antibody-enzyme conjugates:
- Antibody mediated induced proximity for enhancing tumor cell susceptibility
to antibody dependent cell-mediated cytotoxicity (ADCC)
C) Antibody-tri-GalNAC Conjugates (LYTACs):
- LYTACs engage the asialoglycoprotein receptor (ASGPR), a liver-specific
lysosome-targeting receptor, to degrade extracellular proteins in a celltype-
D) Antibody-degrader conjugates:
- Case study 1: Genentech’s antibody-chimeric BET degrader approach and in
vivo activity in blood cancers.
- Case study 2: Antibody-PROTAC conjugates for HER2-Dependent Targeted
Protein Degradation of BRD4