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 (N-benzyl-4-(2-chloroacetyl)-1-methyl-1H-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 IC50 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.