Pre-Conference Workshop Day
Tuesday May 10, 2022
WORKSHOP A
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?
Workshop Leaders:
Radosław Nowak
Senior Scientist
Fischer Lab, Group Leader at the Center for Protein Degradation
Mikołaj Słabicki
Group Leader, Cancer Program, Ebert Lab, Broad Institute Senior Staff Scientist
Dana-Farber Cancer Institute
Shourya S. Roy Burman
Research Fellow
Dr. Eric Fischer’s lab Dana-Farber Cancer Institute & Harvard Medical School
Hojong Yoon
Postdoctoral Associate - Ebert lab
Broad Institute of MIT & Harvard
Networking Break
12:00 - 13:00
WORKSHOP B
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-
specific manner
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
Workshop Leaders
Ed Ha
Head of Chemistry & Bioconjugation
Angiex
Manish Hudlikar
Scientist, Chemistry & Bioconjugates
Angiex
