Degraders & Molecular Glues: Beyond Oncology

Designing and Optimizing PROTACs and Glue Modalities for Diverse Therapeutic Indications

April 14, 2025

Protein degraders and molecular glues are being developed to disrupt protein-protein interactions and to hijack the ubiquitin-proteasome, lysosome, and autophagy systems for targeted protein degradation. While most of the hetero-bifunctional degraders like proteolysis-targeting chimeras (PROTACs) and monovalent degraders like molecular glues are being used to target cancer, there are some headwinds driving non-oncology indications as well. This inaugural symposium that focuses on applications of Degraders & Molecular Glues: Beyond Oncology will be followed by a two-part conference on Degraders & Molecular Glues which emphasizes the growing use of targeted protein degradation and induced proximity as a new therapeutic approach.

Monday, April 14

12:00 pmPre-Conference Symposium Registration

1:00 pmWelcome Remarks

1:10 pm

Chairperson's Remarks

Mary Matyskiela, PhD, Vice President, Molecular Sciences, Neomorph, Inc.

1:15 pm

FEATURED PRESENTATION: Destruction with High Specificity: Mechanisms of Substrate Selection and Processing by the 26S Proteasome and p97/Cdc48

Andreas Martin, PhD, Professor and HHMI Investigator, Molecular & Cell Biology, University of California Berkeley

Our biochemical, single-molecule, and cryo-EM structural studies provide important mechanistic insights into the processing of ubiquitinated substrates by the 26S proteasome and the p97/Cdc48 protein unfoldase. We also recently characterized a novel mode of ubiquitin-independent, NUB1-cofactor mediated degradation by the human proteasome, whereby the ubiquitin-like modifier FAT10 functions in substrate delivery and engagement by the proteasomal ATPase motor, offering new opportunities for targeted protein degradation independent of ubiquitin or p97.

2:15 pm

A Cellular Strategy for Interrogating TPD-Competent Sites on E3 Ligases

Justin M Reitsma, PhD, Principal Research Scientist I, Targeted Protein Degradation, AbbVie Inc

Discovering functionally active ligands within druggable pockets of novel E3 ligases has posed a significant challenge to targeted protein degradation efforts. We address this by using genetic code expansion to engineer ligases containing tetrazine-functionalized non-canonical amino acids. In living cells, click chemistry conjugates the tetrazine with a strained trans-cyclooctene linked to a target-binding ligand. This engineered ligase, featuring a covalent neosubstrate binder, is then analyzed for its protein degradation efficacy.

2:45 pm

Leveraging Generative AI to Develop CRBN Molecular Glue Libraries for Efficient HTS and Rational Design

HongBo Zhang, VP, HitChem

The development of CRBN molecular glue (MG) degraders presents several key challenges: 1. Precision and Innovation in Rational Design – Achieving high precision to minimize off-target risks while incorporating innovative structures to ensure intellectual property (IP) advancement. 2. Optimized HTS Libraries – Designing libraries with validated warhead motifs while maintaining high structural diversity to maximize cost-effectiveness. In this presentation, we will showcase how we have leveraged generative AI to develop a robust molecular generation model and its application in creating CRBN MG libraries—both virtual and ready-to-use. Additionally, we will share case studies demonstrating how the integration of these libraries with CADD tools, and lab chemistry capabilities has successfully led to the identification of novel degrader compounds and the discovery of hit compounds targeting multiple CRBN-degrading proteins.

3:15 pmNetworking Refreshment Break

3:30 pm

Molecular Glue, Mitochondrial Biogenesis, Neurodegeneration, and Aging

Tauseef Butt, PhD, President & CEO, Progenra, Inc.

Misfolded proteins and protein aggregates, such as tau and a synuclein, damage mitochondria leading to cell death. ATP is in high demand by ubiquitin proteasome system to keep the house clean. Progenra has discovered a potent molecular glue that activates Parkin (E3 ligase)/PINK1 (kinase) signaling pathway. Phosphorylation of ubiquitin and parkin E3 ligase by PINK1 orchestrates mitophagy as well as initiating mitochondrial gene transcription and translation (mitobiogenesis). Healthy mitochondrial function plays a critical role in protection against Alzheimer’s and Parkinson’s diseases and aging. Phospho-ubiquitin levels in blood act as a biomarker for healthy aging. Mechanisms of the glue will be discussed.

4:00 pm

Targeting 14-3-3/CRAF Complexes with Molecular Glues: Applications in Oncology and RASopathies

Markella Konstantinidou, PhD, Staff Scientist, Laboratory of Dr. Michelle Arkin, Department of Pharmaceutical Chemistry, University of California, San Francisco

The hub protein 14-3-3 plays a pivotal role in controlling CRAF function in the MAPK pathway. 14-3-3 binds to pS259, maintaining CRAF in an inactive state, thus preventing downstream signaling. Mutations in the residues surrounding the pS259 site occur in developmental disorders termed “RASopathies.” We have developed molecular glues targeting the 14-3-3/CRAF wild-type autoinhibited complex with applications in RAS-driven cancers, as well as molecular glues targeting the mutated RASopathy complexes.

4:30 pm

PANEL DISCUSSION: Session Speakers Discuss Emerging Applications of Degraders & Glues

PANEL MODERATOR:

Mary Matyskiela, PhD, Vice President, Molecular Sciences, Neomorph, Inc.

5:15 pmClose of Symposium

5:30 pmDinner Short Course Registration

6:00 pmDinner Short Course*

SC1: Protein Degraders: A Beyond Rule of Five Space and in vitro ADME Perspective

*Premium Pricing or separate registration required. See Short Courses page for details.