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DUB Drug Discovery: A Platform for Creating DUB-Focused Small Molecules to Regulate Protein Homeostasis in Human Disease

Dana-Farber scientists have developed a drug discovery platform targeting the family of deubiquitinase (DUB) enzymes, which have a critical role in maintaining and recycling proteins in cancer and many other diseases.

Therapeutics

Project Overview

Deubiquitinase enzymes (DUBs) are key players in a foundational pathway to regulate protein stability in the human body. As such, they represent a deep well of underappreciated, new targets for cancer therapeutics.
Dana-Farber scientists have developed a new drug discovery platform to identify compounds that control protein stability by regulating DUB activity and created several small molecule compounds for clinical development.
This DUB-based drug discovery platform will be developed in a new company originating out of the labs at Dana-Farber.

Technology

Sara Buhrlage, PhD, and Jarrod Marto, PhD, at Dana-Farber have developed an innovative drug discovery platform centered on deubiquitinase (DUB) biology. DUBs are a class of approximately 100 enzymes that remove ubiquitin (Ub) from proteins, making them functional partners to the ligases which attach ubiquitin to proteins. Ubiquitination of proteins regulates many crucial biological processes, the most well-known being the promotion of proteasome-mediated protein degradation.

The regulation of the Ub system by ligases and DUBs plays important roles in various cellular processes including protein turnover, cellular homeostasis, and localization of numerous regulatory proteins. Target substrates of DUBs are enzymes, transcription factors, signal transduction molecules, immune response proteins, viral proteins, epigenetic factors, regulators of cell homeostasis, and products of known oncogenes and tumor suppressor genes. Therefore, DUBs have emerged as promising candidates for targeted drug development for many diseases, although today only a small fraction of DUBs have selective chemical ligands.

Being able to influence DUB activity with small molecules has broad applications in both clinical and research settings. Significant efforts have been made to develop effective and specific DUB inhibitors with limited success

Unfortunately, DUBs are an historically under-studied family and no systematic interrogation of the family had been attempted prior to Buhrlage and Marto’s efforts. To design safe and effective therapeutics, they needed to map the function and activity of not just a single DUB, but the entire family as a class.

To address the need for targeted DUB drug discovery, the Buhrlage/Marto team created a DUB-focused platform to develop selective inhibitors to understand both the function of any given DUB as well as its potential as a target for treating disease. Their goal is to improve the understanding of this large and important family of proteins and their role in various diseases and use this information to develop new therapies.

To accelerate the development of DUB-targeted therapeutics, the team’s DUBs platform includes three components:

Proprietary screening tools, starting with a chemo-diverse library of DUB-targeted small molecules to selectively and specifically modulate the function of DUBs.
A critical path of high-throughput, activity-based assays and other DUB-focused assays that generate high-content data measuring the effects of DUB modulation in cell–based systems
Data analytics that reveal the relationships between DUBs, disease pathways, and clinical applications, helping to identify DUBs involved in specific diseases

Using this platform described in a 2023 Nature Communications paper, the team has identified selective modulators for 23 DUBs across four subfamilies. These compounds have been advanced to cell studies, generating extremely rich and detailed data regarding the direct and downstream effects of DUB modulation in both healthy and cancerous cells. This work includes the first known selective inhibitors for several DUBs, and the identification of novel DUB-disease links that serve as the entry point to new therapeutic discovery projects.

DUBs and Their Studied Pathways

Team Members: Sara Buhrlage, PhD, Jarrod Marto, PhD

Applications

One of the team’s lead DUB inhibitors targets USP7 and stabilizes the p53 tumor suppressor protein, one of the most commonly inactivated genes in cancer. This inhibitor has potential applications in various adult cancers, including renal cell carcinoma, melanoma, rhabdoid sarcoma, multiple myeloma, and liposarcoma.

The compound also shows promise in treating Ewing Sarcoma, a pediatric cancer caused by a fusion protein called EWS/FLI. This fusion protein has historically been a challenging drug target. Since the current standard treatment involves intensive combination chemotherapy, surgery, and radiation, inhibiting DUBs could offer an alternative treatment strategy.

Interested in learning more?

Accelerating inhibitor discovery for deubiquitinating enzymes

Nature Communications paper

Opportunities

The DUB-focused small molecule drug discovery program will be developed in a new company established from the labs of Dana-Farber.

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