USP7

 

USP7

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 characterized role is the removal of ubiquitin from the oncogene MDM2 and thus regulating the tumor suppressor protein p53 2

It has also been shown to deubiquitinate other substrates including N-MYC 3 and Histone H2B 4 as well several tumor 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 program at Almac Discovery is progressing towards pre-clinical candidate nomination.

  1. Clague, M. J., Urbe, S. & Komander, D. Breaking the chains: deubiquitylating enzyme specificity begets function. Nat Rev Mol Cell Biol 20, 338-352 (2019).
  2. 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).
  3. Tavana, O. et al. HAUSP deubiquitinates and stabilizes N-Myc in neuroblastoma. Nat Med 22, 1180-1186 (2016).
  4. 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).
  5. Schauer, N. J. et al. Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism. Sci Rep 10, 5324 (2020).
  6. Gavory, G. et al. Discovery and characterization of highly potent and selective allosteric USP7 inhibitors. Nat Chem Biol 14, 118-125 (2018).
  7. O’Dowd, C. R. et al. Identification and Structure-Guided Development of Pyrimidinone Based USP7 Inhibitors. ACS Med Chem Lett 9, 238-243 (2018).
  8. 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).
  9. Turnbull, A. P. et al. Molecular basis of USP7 inhibition by selective small-molecule inhibitors. Nature 550, 481-486 (2017).
  10. 10. Kategaya, L. et al. USP7 small-molecule inhibitors interfere with ubiquitin binding. Nature 550, 534-538 (2017).

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