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Discovery of a Potent Fluorescence Polarization Probe for Identifying USP1 Allosteric Inhibitors
Jiawei Cheng1,2, Peipei Wang3, Pengfei Wang2,4,5
1Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|April 22, 2026
Summary
Researchers developed a novel fluoroprobe and fluorescence polarization assay to discover ubiquitin-specific protease 1 (USP1) inhibitors for cancer therapy. This tool identified potent new USP1 inhibitors with strong anti-cancer effects.
Area of Science:
- Biochemistry
- Chemical Biology
- Oncology
Background:
- Ubiquitin-specific protease 1 (USP1) is overexpressed in many cancers, presenting a therapeutic target.
- USP1 allosteric inhibitors offer high selectivity and potency for cancer treatment.
- Lack of chemical tools hinders the discovery of novel USP1 allosteric ligands.
Purpose of the Study:
- To develop the first allosteric fluoroprobe and fluorescence polarization (FP) assay for direct validation of USP1 allosteric inhibitors.
- To establish a robust and scalable tool for high-throughput screening of USP1 inhibitors.
- To identify novel USP1 inhibitors with potential therapeutic applications.
Main Methods:
- Development of an allosteric fluoroprobe for USP1.
- Establishment of a fluorescence polarization (FP) assay utilizing the fluoroprobe.
- Screening of compounds to identify novel USP1 inhibitors.
- In vitro enzymatic and cellular assays.
- In vivo efficacy studies in DLBCL models.
Main Results:
- The developed FP assay successfully differentiated between allosteric and catalytic site inhibitors.
- A novel class of potent tetrahydroisoquinoline USP1 inhibitors was identified.
- Compound 14a demonstrated superior enzymatic and cellular activity compared to KSQ-4279.
- Compound 14a showed potent in vivo anti-DLBCL efficacy and favorable druggability.
Conclusions:
- The study provides a valuable fluoroprobe and FP assay platform for USP1 inhibitor discovery.
- Novel potent USP1 inhibitors, including compound 14a, were identified.
- These findings offer promising lead compounds for further structural optimization and antitumor mechanism studies targeting USP1.
