How a Heart Medication Could Unlock a New Non-Toxic Cancer Treatment Strategy

Researchers have uncovered a new way to attack lymphoma by targeting a non-catalytic region of a key regulatory enzyme, rather than its traditional active site.

Researchers at VCU Massey Comprehensive Cancer Center found a surprising new angle for fighting lymphoma using a medication that is already approved for abnormal heart rhythms.

Instead of treating cancer cells with a broad toxic hit, the approach aims at a specific set of enzyme functions that lymphoma cells rely on. In tests, the strategy wiped out cancer cells and slowed tumor growth with little to no toxicity. The work, reported in Pharmacological Research, points to a new direction for precision medicine in cancer by focusing on a part of the target that most drug programs have ignored.

“These findings redefine our understanding of the USP11 enzyme and shed light on the anti-tumor effects of RBF4—an existing heart medication—illuminating a new therapeutic approach in lymphoid malignancies and beyond,” said study senior author Ronald Gartenhaus, M.D., associate director for veterans health at Massey and director of the Richmond VA Cancer Center.

Rethinking How to Target Cancer Enzymes

USP11 is part of the deubiquitinase family, or (DUB), a class of enzymes that help control protein stability inside cells. You can think of this system as cellular quality control. Proteins are constantly being tagged, untagged, and routed for reuse or breakdown, and DUB enzymes help remove those tags to keep the balance. Because cancer cells are unusually dependent on these protein control circuits, DUBs have long looked like appealing targets.

Most attempts to block DUBs have gone after the catalytic active site, the region where the chemistry happens. That has been a tough road. Many DUBs share very similar active site structures, so a compound designed for one enzyme can accidentally inhibit others. On top of that, many active site inhibitors have struggled with properties that make them less effective in living systems.

A New Therapeutic Strategy Emerges

Instead of trying to shut down USP11 by plugging its catalytic machinery, the VCU team aimed at its ubiquitin like (UBL) domain. This region does not carry out the chemical reaction. It acts more like a scaffolding surface that helps USP11 connect with partner proteins. Targeting this domain gave the researchers a way to use structural details that are more unique to USP11, helping separate it from closely related enzymes such as USP4 and USP15.

“This study establishes a new paradigm for targeting non-enzymatic functions in tumor cells and positions the molecules RBF4 and RBF11 as first-in-class prototypes that could lay the foundation for the next generation of precision medicine for cancer,” said study co-author Bandish Kapadia, Ph.D., an assistant professor at the VCU School of Medicine. “By focusing on USP11’s scaffolding functions rather than its catalytic activity, we’ve unlocked a new therapeutic vulnerability in aggressive cancers.”

Glen E. Kellogg, Ph.D., professor emeritus at the VCU School of Pharmacy, led a structure-based virtual screening effort that sifted through more than 10 million compounds to identify candidates predicted to bind the USP11 scaffolding domain. That search ultimately led to RBF4.

In follow-up testing, the inhibitors showed strong activity against diffuse large B cell lymphoma cells while largely sparing normal cells, a pattern that supports the goal of selectively disrupting cancer biology without widespread damage.

Implications for Lymphoma Treatment

Lymphoma is a cancer that starts in cells that are part of the body’s immune system. Diffuse large B-cell lymphoma is the most common and fast-growing type of non-Hodgkin lymphoma, accounting for approximately one in every three lymphomas, according to the American Cancer Society.

In relevant preclinical models of MYC-driven lymphoma, RBF4 significantly reduced tumor growth, prevented metastatic spread, and inhibited fluid accumulation, all without observable damage to surrounding tissue.

RBF4 was found to be chemically identical to dronedarone, an FDA-approved medication used to treat irregular heartbeat. This serendipitous discovery opens the possibility of repurposing an existing drug for cancer treatment, potentially accelerating the path to clinical trials by leveraging established safety data.

“The fact that this molecule has already been used without significant toxicities in patients was reassuring because now we know that it can already be used safely and effectively for certain patients in the clinical setting,” said Gartenhaus, whose lab has been studying RNA translation and lymphoma for decades.

Building on Earlier Discoveries

This work builds on previous research from Kapadia and Gartenhaus, published in Nature Communications, which demonstrated that USP11 plays a critical role in controlling protein production in lymphoma cells, making it an attractive therapeutic target.

Looking ahead, the researchers are collaborating with Victor Yazbeck, M.D., a hematologist-oncologist, in an effort to investigate the efficacy of RBF4 for lymphoma through clinical trials at Massey. If RBF4 is found effective through initial clinical trials, there is reasonable evidence to suggest that the drug could target a wide range of other tumors, where USP11 has previously been implicated in breast, cervical, colorectal, esophageal, liver, ovarian, and pancreatic cancers, among others.

Reference: “Discovery, development, and characterization of potent and selective USP11 inhibitors” by Forum Kayastha, Noah B. Herrington, Anirban Roychowdhury, Nahid M. Nanaji, Won Sok Lee, Glen E. Kellogg, Bandish Kapadia and Ronald B. Gartenhaus, 27 December 2025, Pharmacological Research.
DOI: 10.1016/j.phrs.2025.108075

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