Discovery, development, and characterization of potent and selective USP11 inhibitors

Pharmacol Res. 2026 Jan:223:108075. doi: 10.1016/j.phrs.2025.108075.

Forum Kayastha ¹, Noah B Herrington ², Anirban Roychowdhury ¹, Nahid M Nanaji ³, Won Sok Lee ⁴, Glen E Kellogg ⁵, Bandish Kapadia ⁶, Ronald B Gartenhaus ⁷

Affiliations

1 Division of Hematology, Oncology, and Palliative Care, Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States; Section of Hematology and Oncology, Medicine Service, Richmond VA Cancer Center, Richmond Veteran Affairs Medical Center, Richmond, VA, United States; VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, United States.
2 Department of Medicinal Chemistry, Center for Drug Discovery and Development, Virginia Commonwealth University School of Pharmacy, Richmond, VA, United States.
3 Department of Veterans Affairs, Maryland Healthcare System, Baltimore, MD, United States.
4 Department of Pathology and Laboratory Medicine, Richmond Veterans Affairs Medical Center, Richmond, VA, United States.
5 VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, United States; Department of Medicinal Chemistry, Center for Drug Discovery and Development, Virginia Commonwealth University School of Pharmacy, Richmond, VA, United States.
6 Division of Hematology, Oncology, and Palliative Care, Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States; Section of Hematology and Oncology, Medicine Service, Richmond VA Cancer Center, Richmond Veteran Affairs Medical Center, Richmond, VA, United States; VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, United States; Richmond Institute of Veterans Research, Richmond, VA, United States. Electronic address: [email protected].
7 Division of Hematology, Oncology, and Palliative Care, Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States; Section of Hematology and Oncology, Medicine Service, Richmond VA Cancer Center, Richmond Veteran Affairs Medical Center, Richmond, VA, United States; VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, United States. Electronic address: [email protected].

PMID: 41461277 DOI: 10.1016/j.phrs.2025.108075

Abstract

Deubiquitinases (DUBs) have long been viewed through the narrow lens of enzymatic catalysis, but emerging evidence reveals their non-catalytic domains as master regulators of oncogenic signaling. USP11, a structurally modular DUB, exemplifies this duality: beyond its canonical role in DNA repair, USP11 scaffolds key translational effectors such as eIF4B, sustaining the expression of pro-survival oncogenes in aggressive lymphomas. Here, we unveil RBF4 and RBF11, first-in-class, non-catalytic USP11 inhibitors discovered through pharmacophore-guided virtual screening anchored on the UBL domain interface. These small molecules selectively bind USP11 without disrupting its catalytic activity yet interrupt critical interactions essential for eIF4B stabilization and oncogenic translation. Mechanistically, USP11 inhibition collapses MYC-driven translational networks, destabilizes DNA repair factors, rewires calcium homeostasis, and induces a post-transcriptional apoptotic program while sparing non-malignant cells. RBF4, chemically identical to the FDA-approved anti-arrhythmic agent Dronedarone, exhibits potent antitumor efficacy in orthotopic EμMyc lymphoma models, suppressing tumor growth, metastatic spread, and ascites formation with no overt toxicity. Transcriptomic analyses reveal broad rewiring of EMT, immune, and metabolic programs, underscoring USP11's role as a nodal regulator of tumor cell identity and plasticity. These findings establish the UBL domain of USP11 as a druggable scaffold, redefining DUBs not merely as Enzymes but as structural signaling platforms. RBF4 emerges as a clinically actionable prototype for dismantling USP11-driven oncogenic circuits, illuminating a new therapeutic axis in lymphoid malignancies and beyond. ONE SENTENCE SUMMARY: Potent, selective USP11 inhibitors exhibit anti-tumor activity.

Keywords

DRUG targets/oncoprotein & tumor suppressor drug targets; Drug discovery technologies/drug discovery technologies; Gene regulation/posttranscriptional and translational control; Hematological cancers/lymphomas.

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