XL177A is a selective irreversible USP7 inhibitor(IC50 : 0.34 nM). XL177A elicits cancer cell killing through a p53-dependent mechanism.

XL177A irreversibly inhibits USP7 with sub-nM potency and selectivity across the human proteome.?Evaluation of the cellular effects of XL177A reveals that selective USP7 inhibition suppresses cancer cell growth predominantly through a p53-dependent mechanism:?XL177A specifically upregulates p53 transcriptional targets transcriptome-wide, hotspot mutations in TP53 but not any other genes predict response to XL177A across a panel of ~500 cancer cell lines, and TP53 knockout rescues XL177A-mediated growth suppression of TP53 wild-type (WT) cells.?Together, these findings suggest TP53 mutational status as a biomarker for response to USP7 inhibition.?We find that Ewing sarcoma and malignant rhabdoid tumor (MRT), two pediatric cancers that are sensitive to other p53-dependent cytotoxic drugs, also display increased sensitivity to XL177A.