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

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Oncology

Background:

• Ubiquitin-specific protease 11 (USP11) is a validated target for cancer therapy.
• Developing selective USP11 inhibitors is challenging due to structural similarities with paralogs like USP4 and USP15.
• Previous covalent probes showed poor selectivity, inhibiting USP4 more potently than USP11.

Purpose of the Study:

• To design and synthesize novel, selective inhibitors of USP11.
• To evaluate the inhibitory potency and selectivity of new compounds against USP11 and its paralogs.
• To assess the anticancer efficacy and cellular effects of lead compounds in relevant cancer cell lines.

Main Methods:

• Structure-based design and chemical synthesis of USP11 inhibitors derived from a known covalent probe.
• Enzyme inhibition assays (IC50 determination) against USP11, USP4, and USP15.
• Jump dilution assay to confirm sustained inhibition and covalent binding.
• Cell proliferation assays using ovarian (PEO4) and breast (MDA-MB-231) cancer cell lines, and normal fibroblasts (MRC-5).

Main Results:

• Compound 7 (IC50 = 2.59 μM) and compound 26 demonstrated potent USP11 inhibition.
• Compounds 7 and 26 exhibited significantly lower activity against USP4 and USP15, indicating high selectivity.
• Both compounds inhibited cancer cell proliferation, with compound 26 showing cytostatic effects and sparing normal fibroblasts.

Conclusions:

• Compounds 7 and 26 are effective and selective USP11 inhibitors.
• These compounds demonstrate potential as valuable tool compounds for biological research.
• Compounds 7 and 26 represent promising candidates for the development of novel USP11-targeted cancer therapeutics.