2025 ARCHIVES

Cambridge Healthtech Institute’s 4th Annual

Covalent & Induced Proximity-Based Therapies

Innovative Chemistries and Assays for Studying and Modulating Cellular Interactions

April 14, 2025 ALL TIMES PDT

Chemically induced proximity is an emerging area of interest, and covalent chemistries are often tapped into to trigger biological interactions, such as for protein degradation, protein stabilization, protein folding, chromatin regulation, and more. Cambridge Healthtech Institute’s symposium on Covalent & Induced Proximity-Based Therapies brings together academic and industry scientists from medicinal chemistry, chemical biology, and proteomics groups to discuss the innovative chemistries and technologies that can be leveraged to induce proximity for mechanistic studies, as well as for therapeutic intervention. It offers a preview of the topics that will be discussed in the conferences on Degraders & Molecular Glues as well as Protein-Protein Interactions that follow.

Monday, April 14

12:00 pmPre-Conference Symposium Registration

1:00 pmWelcome Remarks

1:10 pm

Chairperson's Remarks

Daniel A. Erlanson, PhD, Chief Innovation Officer, Frontier Medicines Corporation

1:15 pm

Hydralazine Covalently Inhibits Cysteamine Dioxygenase to Attenuate GPCR Signaling and Glioblastoma Growth

Megan Matthews, PhD, Assistant Professor, Department of Chemistry, University of Pennsylvania

The vasodilator, hydralazine (HYZ), has been used clinically for 70 years, but its mechanism of action is still unknown. We show that HYZ covalently and irreversibly inhibits 2-aminoethanethiol dioxygenase (ADO) and explains the drugs MOA for preeclampsia. The drug binds in a bidentate fashion to the enzyme’s metal cofactor, resulting in alkylation of the histidine ligand. Mechanism-based inactivation of ADO by HYZ senesces glioblastoma cells. The results connect an old drug to its target, reveal the mechanism of its therapeutic effect, and imply that it might be repurposed and further optimized for the treatment of a deadly brain cancer.

1:45 pm

Identification of VVD-214/RO7589831: A Clinical-Stage, Covalent Allosteric Inhibitor of WRN Helicase for the Treatment of MSI-High Cancers

Shota Kikuchi, PhD, Director, Chemistry, Vividion Therapeutics

WRN helicase is a promising target for treating cancers with microsatellite instability (MSI) due to its essential role in resolving deleterious non-canonical DNA structures that accumulate in cells with faulty mismatch repair mechanisms. Here we describe the medicinal chemistry optimization of potency, ADME, and PK properties of chemoproteomic screening hits, which resulted in identification of VVD-214/RO7589831 (Vividion/Roche), a clinical-stage, covalent allosteric inhibitor of WRN.

2:15 pm

Discovery of RAS(ON) Mutant-Selective Covalent Tri-Complex Inhibitors

Allison Zhang, PhD, Senior Scientist I, Structural Biology & Biophysics, Revolution Medicines

We designed a series of natural product-inspired molecules that bind and remodel the surface of cyclophilin A to create a binary complex with high affinity for the active, GTP bound (ON) state of RAS. The resulting tri-complex sterically blocks RAS-effector interactions to disrupt downstream signaling. Structure-guided optimization enabled the development of orally bioavailable covalent inhibitors including the investigational agents, RMC-6291 (RAS(ON) G12C-selective) and RMC-9805 (RAS(ON) G12D-selective), both of which display profound antitumor activity in preclinical models.

2:45 pm

In-Solution Quantification of Small-Molecule Protein Interactions Using FIDA Lambda Dynamics in Drug Discovery

David Myszka, Dir Drug Discovery, Biosensor Tools

Based on “1st principle” biophysics, Flow Induced Dispersion Technology (FIDA) bridges the gap between structural and functional information of biomolecules. FIDA developed the capability of generating kon and koff rates in a fully in-solution assay without any immobilization to surfaces. Fida is able to measure in-solution small-molecule binding with 3 different orthogonal measurements in addition to quantifying molecule sizing (hydrodynamic radius), aggregation, PDI, and viscosity.

3:00 pm

QuValent: QM/MM FEP & Transition State Analysis for Covalent Drug Design with Pharma-Suitable Throughput

David Pearlman, VP Product, Product, QSimulate

Despite increasing interest in covalent drugs, computational tools to help in lead optimization have lagged, due to the inherently quantum nature of covalent bond formation. We have developed the first QM/MM-based approach to FEP allowing throughput with a cost and timescale suitable for commercial drug discovery. QuValent allows far better predictions than classical methods. A complementary automated platform for assessing transition state energetics similarly provides for warhead optimization.

3:15 pmNetworking Refreshment Break

3:30 pm

Covalent Fragment-Based Ligand Discovery to Drug-Refractory Targets

Joe Patel, PhD, Vice President and Head of Discovery, Nexo Therapeutics

The presentation will discuss the design of CODON, our proprietary pan-amino-acid covalent fragment library and its ability to identify novel and induced pockets on relevant protein targets. The rich SAR generated during the screening phase enables rapid hit-to-lead progression and early confirmation of cellular target engagement.

4:00 pm

Discovery and Characterization of Covalent Inhibitors

Brooke Brauer, PhD, Senior Research Scientist, Mass Spectrometry, AstraZeneca Pharmaceuticals

Covalent modulation of therapeutic targets is an increasingly important modality for drug discovery, particularly after recent success with historically challenging targets like KRAS G12C. In this talk, I’ll present the work we have done to discover covalent inhibitors for an anti-apoptotic protein target and the targeted proteomics work done to profile the lead compounds effect in cells.

4:30 pm

FEATURED PRESENTATION: Drug Discovery by Developing Heterobifunctional Molecules as Regulated Induced Proximity Targeting Chimeras (RIPTACs)

Jia Zhou, PhD, Professor, Chemical Biology Program, Department of Pharmacology & Toxicology, University of Texas Galveston

RIPTACs show promise in specifically targeting and eliminating disease cells while leaving healthy cells unharmed. As a unique drug discovery approach, RIPTACs work by forming a stable complex with two proteins, one specifically found in disease cells (target protein, TP) and the other pan-essential for cell survival (effector protein, EP), selectively disrupting the EP function in disease cells, causing cell death. Intriguingly, the TPs need not be linked to disease progression, broadening the spectrum of potential drug targets. This presentation will introduce the proof of concept of the RIPTAC strategy and our efforts developing such heterobifunctional molecules as potential therapeutics.

5:15 pmClose of Symposium

5:30 pmDinner Short Course Registration

6:00 pmDinner Short Course*

SC2: Fragment-Based Drug Design: Advancing Tools and Technologies

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