Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism

by Selleckchem | Oct 10 2023

Ubiquitin specific peptidase 7 (USP7) is a deubiquitinating enzyme (DUB) that removes ubiquitin tags from specific protein substrates in order to alter their degradation rate and sub-cellular localization. USP7 has been proposed as a therapeutic target in several cancers because it has many reported substrates with a role in cancer progression, including FOXO4, MDM2, N-Myc, and PTEN. The multi-substrate nature of USP7, combined with the modest potency and selectivity of early generation USP7 inhibitors, has presented a challenge in defining predictors of response to USP7 and potential patient populations that would benefit most from USP7-targeted drugs. Here, we describe the structure-guided development of XL177A, which 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.

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Thank you for sharing this information about Ubiquitin specific peptidase 7 (USP7) and its potential as a therapeutic target in cancer. It seems that USP7 has been implicated in cancer progression due to its ability to modify the degradation rate and sub-cellular localization of various protein substrates involved in cancer, such as FOXO4, MDM2, N-Myc, and PTEN.

The development of XL177A, a USP7 inhibitor, has been guided by the protein's structure and has resulted in a potent and selective compound that irreversibly inhibits USP7 with sub-nanomolar (nM) potency. This inhibitor has been evaluated for its effects on cancer cells and has been found to predominantly suppress cancer cell growth through a p53-dependent mechanism. XL177A specifically upregulates the transcriptional targets of p53 throughout the entire transcriptome, indicating its impact on p53 signaling.

Interestingly, the response to XL177A seems to be associated with the mutational status of TP53, the gene that encodes the p53 protein. Hotspot mutations in TP53, but not mutations in other genes, have been identified as predictors of response to XL177A across a panel of approximately 500 cancer cell lines. Moreover, when TP53 is knocked out, the growth suppression mediated by XL177A in TP53 wild-type cells is rescued, further supporting the involvement of p53 in the cellular effects of the USP7 inhibitor.

Additionally, XL177A has shown increased sensitivity in two pediatric cancers, namely Ewing sarcoma and malignant rhabdoid tumor (MRT), both of which are known to be responsive to other p53-dependent cytotoxic drugs. This suggests that XL177A could be a potential treatment option for these particular cancer types as well.

Overall, these findings propose TP53 mutational status as a biomarker for the response to USP7 inhibition and highlight the potential of XL177A as a targeted therapeutic agent in various cancers, particularly those with p53 involvement and sensitivity to p53-dependent treatments.