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

XL177A has a similar USP7 binding mode to XL188

Schauer et al. (2020) Sci Rep. CC BY 4.0

Schauer NJ, Liu X, Magin RS, Doherty LM, Chan WC, Ficarro SB, Hu W, Roberts RM, Iacob RE, Stolte B, Giacomelli AO, Perera S, McKay K, Boswell SA, Weisberg EL, Ray A, Chauhan D, Dhe-Paganon S, Anderson KC, Griffin JD, Li J, Hahn WC, Sorger PK, Engen JR, Stegmaier K, Marto JA, Buhrlage SJ.

Scientific Reports

March 24, 2020

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.

Last updated: July 19, 2020