STRUCTURE-GUIDED DESIGN OF NOVEL PYRAZOLE CARBAMATES AS USP7 INHIBITORS

Ubiquitin-specific protease 7 (USP7) is a key regulator of multiple cellular pathways, including immune response, epigenetic regulation, viral replication, apoptosis, and DNA damage response. Aberrant USP7 expression is implicated in several pathological conditions, notably cancer, making USP7 an attractive pharmacological target for the development of novel therapeutic strategies. In the last years, we designed and synthesized a series of pyrazolyl-ureas and pyrazole-carbamates endowed with anticancer activities and significant USP7 inhibitory potency. More specifically, derivatives STIRUR-41 and I proved to be the most active compounds showing IC50 values in the low micromolar range against recombinant USP7 (1.31-2.77 µM) and being able to inhibit the migration of HTLA-230 neuroblastoma cells without affecting normal fibroblasts. To extend the structure-activity relationships (SARs) of lead derivatives I, we designed and prepared novel compounds 1-3 bearing different substitution on the carbamate phenyl moiety and an amino phenyl or S-methyl substituent at position 3 of the pyrazole ring. Pyrazoles 1-3 were prepared through a stepwise approach and screened against recombinant USP7 as racemic mixtures. Additionally, the cytotoxicity of the compounds was evaluated against a panel of cancer and normal cell lines. Selected molecules of the series displayed improved inhibitory profile in comparison with the reference derivatives I, thus validating the adopted SAR strategy and providing useful indication for further studies.