Cambridge Healthtech Institute’s Inaugural

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 PM

Pre-Conference Symposium Registration

EXPLORING NEW DEGRADATION PATHWAYS & MODALITIES

1:00 PM

Welcome Remarks

1:10 PM

Chairperson's Remarks

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

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

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

Networking Refreshment Break

3:30 PM

Molecular Glue, Mitochondrial Biogenesis, Neurodegeneration, and Aging

Photo of Tauseef Butt, PhD, President & CEO, Progenra, Inc. , President & CEO , Progenra Inc — Tauseef Butt, PhD, President & CEO, Progenra, Inc. , 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 Alzheimerâ€™s and Parkinsonâ€™s diseases and aging. Phospho-ubiquitin levels in blood act as a biomarker for healthy aging. Mechanisms of the glue will be discussed.Â

4:00 PM

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

Photo of Markella Konstantinidou, PhD, Staff Scientist, Laboratory of Dr. Michelle Arkin, Department of Pharmaceutical Chemistry, University of California, San Francisco , Staff Scientist , Pharmaceutical Chemistry , University of California, San Francisco — Markella Konstantinidou, PhD, Staff Scientist, Laboratory of Dr. Michelle Arkin, Department of Pharmaceutical Chemistry, University of California, San Francisco , Staff Scientist , 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 â€œRASopathies.â€ 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.