Ubiquitin specific protease 7 (USP7) is a member of the deubiquitinating enzyme class that contains 106 representatives in human cells. USP7 removes the post-translational tag ubiquitin from several protein targets 1.
USP7 best characterised role is the removal of ubiquitin from the oncogene MDM2 and thus regulating the tumour suppressor protein p53 2.
It has also been shown to deubiquitinate other substrates including N-MYC 3 and Histone H2B 4 as well several tumour promoters and immune modulators , highlighting strong disease linkages in oncology. It’s main attraction as a therapeutic target has been linked to the modulation of the p53-MDM2 axis but also in modulating the immune response 5.
Recently, breakthroughs have been made by Almac Discovery 6 7 and others 8 9 10 in the discovery of highly potent and selective USP7 inhibitors, providing powerful pharmacological tools for further USP7 biology exploration. The USP7 programme at Almac Discovery is progressing towards pre-clinical candidate nomination.
- Clague, M. J., Urbe, S. & Komander, D. Breaking the chains: deubiquitylating enzyme specificity begets function. Nat Rev Mol Cell Biol 20, 338-352 (2019).
- Tavana, O. & Gu, W. Modulation of the p53/MDM2 interplay by HAUSP inhibitors. J Mol Cell Biol 9, 45-52, doi:10.1093/jmcb/mjw049 (2017).
- Tavana, O. et al. HAUSP deubiquitinates and stabilizes N-Myc in neuroblastoma. Nat Med 22, 1180-1186 (2016).
- van der Knaap, J. A. et al. GMP synthetase stimulates histone H2B deubiquitylation by the epigenetic silencer USP7. Mol Cell 17, 695-707, doi:10.1016/j.molcel.2005.02.013 (2005).
- Schauer, N. J. et al. Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism. Sci Rep 10, 5324 (2020).
- Gavory, G. et al. Discovery and characterization of highly potent and selective allosteric USP7 inhibitors. Nat Chem Biol 14, 118-125 (2018).
- O’Dowd, C. R. et al. Identification and Structure-Guided Development of Pyrimidinone Based USP7 Inhibitors. ACS Med Chem Lett 9, 238-243 (2018).
- Lamberto, I. et al. Structure-Guided Development of a Potent and Selective Non-covalent Active-Site Inhibitor of USP7. Cell Chemical Biology 24, 1490 (2017).
- Turnbull, A. P. et al. Molecular basis of USP7 inhibition by selective small-molecule inhibitors. Nature 550, 481-486 (2017).
- 10. Kategaya, L. et al. USP7 small-molecule inhibitors interfere with ubiquitin binding. Nature 550, 534-538 (2017).