Work

Design, Synthesis, and Evaluation of Selective Ubiquitin-Specific Protease 11 (USP11) Inhibitors

Year: 2025

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide Ubiquitin-specific protease 11 (USP11) is a promising anticancer target, but selective inhibitor development has proved to be challenging. Here, we designed and synthesized selective USP11 inhibitors based on a previously reported covalent probe ( N -benzyl-4-(2-chloroacetyl)-1-methyl-1 H -pyrrole-2-carboxamide, compound 2 ) that is a more potent inhibitor of USP4 than USP11. Compound 7, derived from 2 by the introduction of a piperidine moiety, exhibited an IC 50 of 2.59 μM, while the replacement of chloroacetyl with a methyl sulfonylpiperazine moiety (compound 26 ) displayed equivalent potency. Sustained inhibition of USP11 consistent with covalent binding was observed in a jump dilution assay, and the compounds displayed significantly lower activity against the paralogues USP4 and USP15. Both compounds inhibited the proliferation of PEO4 ovarian and MDA-MB-231 breast cancer cells. Notably, compound 26 displayed cytostatic activity, and normal fibroblast MRC-5 cells were less affected. The findings highlight the potential of 7 and 26 as promising candidates for the development of selective tool compounds and therapeutic agents targeting USP11.

Source: ACS Omega

DOI: 10.1021/acsomega.5c08248

Authors: Mostafa A. Hassan, Lodewijk V. Dekker, Michael J. Stocks, Ingrid Dreveny

Institutions: University of Nottingham, Assiut University

Language: English

Topic: Ubiquitin and proteasome pathways

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $1,935