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

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 (<i>N</i>-benzyl-4-(2-chloroacetyl)-1-methyl-1<i>H</i>-pyrrole-2-carboxamide, compound <b>2</b>) that is a more potent inhibitor of USP4 than USP11. Compound <b>7</b>, derived from <b>2</b> by the introduction of a piperidine moiety, exhibited an IC₅₀ of 2.59 μM, while the replacement of chloroacetyl with a methyl sulfonylpiperazine moiety (compound <b>26</b>) 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 <b>26</b> displayed cytostatic activity, and normal fibroblast MRC-5 cells were less affected. The findings highlight the potential of <b>7</b> and <b>26</b> as promising candidates for the development of selective tool compounds and therapeutic agents targeting USP11.