Novel, Selective Inhibitors of USP7 Uncover Multiple Mechanisms of Antitumor Activity and .

The deubiquitinase USP7 regulates the levels of multiple proteins with roles in cancer progression and immune response. Thus, USP7 inhibition may decrease oncogene function, increase tumor suppressor function, and sensitize tumors to DNA-damaging agents. We have discovered a novel chemical series that potently and selectively inhibits USP7 in biochemical and cellular assays. Our inhibitors reduce the viability of multiple wild-type cell lines, including several hematologic cancer and -amplified neuroblastoma cell lines, as well as a subset of -mutant cell lines Our work suggests that USP7 inhibitors upregulate transcription of genes normally silenced by the epigenetic repressor complex, polycomb repressive complex 2 (PRC2), and potentiate the activity of PIM and PI3K inhibitors as well as DNA-damaging agents. Furthermore, oral administration of USP7 inhibitors inhibits MM.1S (multiple myeloma; wild type) and H526 (small cell lung cancer; mutant) tumor growth Our work confirms that USP7 is a promising, pharmacologically tractable target for the treatment of cancer.