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 TP53 wild-type cell lines, including several hematologic cancer and MYCN-amplified neuroblastoma cell lines, as well as a subset of TP53-mutant cell lines in vitro. 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; TP53 wild type) and H526 (small cell lung cancer; TP53 mutant) tumor growth in vivo. Our work confirms that USP7 is a promising, pharmacologically tractable target for the treatment of cancer.

中文翻译：

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USP7 的新型选择性抑制剂揭示了体外和体内抗肿瘤活性的多种机制

去泛素化酶 USP7 调节多种蛋白质的水平，这些蛋白质在癌症进展和免疫反应中发挥作用。因此，USP7 抑制可能会降低癌基因功能，增加肿瘤抑制功能，并使肿瘤对 DNA 损伤剂敏感。我们发现了一种新型化学系列，可在生化和细胞分析中有效且选择性地抑制 USP7。我们的抑制剂降低了多种 TP53 野生型细胞系的活力，包括几种血液癌症和 MYCN 扩增的神经母细胞瘤细胞系，以及体外 TP53 突变细胞系的一个子集。我们的工作表明，USP7 抑制剂上调通常被表观遗传抑制复合物、多梳抑制复合物 2 (PRC2) 沉默的基因的转录，并增强 PIM 和 PI3K 抑制剂以及 DNA 损伤剂的活性。此外，口服 USP7 抑制剂可抑制 MM.1S（多发性骨髓瘤；TP53 野生型）和 H526（小细胞肺癌；TP53 突变体）体内肿瘤生长。我们的工作证实，USP7 是一种有前途的、药理学上易于处理的癌症治疗靶点。