Structure-activity relationship analysis of a Pyrrolo-Phenylamidine scaffold as a chemotype for ubiquitin-specific protease 11 (USP11) inhibition

초록

Ubiquitin-specific protease 11 (USP11) is a deubiquitinating enzyme implicated in diverse disease-related signaling pathways, yet well-characterized chemical probes for this target remain limited. Here, we report a structure-activity relationship (SAR) study of a pyrrolo-phenylamidine scaffold as a chemotype for USP11 inhibition. A focused library of analogues was designed and synthesized to define key binding determinants, revealing the pyrrolo-amidine moiety as an essential element, while the terminal phenyl group primarily contributes to hydrophobic stabilization. These SAR trends were supported by molecular docking and molecular dynamics simulations. Representative compounds exhibited low micromolar USP11 inhibitory activity, with a modest preference over the closely related USP15, and reduced TGF-(3-induced transcription in a cellular reporter assay at non-cytotoxic concentrations, consistent with their enzymatic potency; higher concentrations were associated with cytotoxicity. Together, these findings identify a promising chemical scaffold for the development of USP11-directed chemical tools and provide a basis for future structure-based optimization.

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