C19: Ubiquitin-specific protease

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Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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The ubiquitin specific peptidases (USPs) are deubiquitinating enzymes (DUBs) that cleave ubiquitin from target proteins. In humans there are ~100 DUBs, that are classified as either cysteine proteases or metalloproteases. There are 58 (human) USPs in the cysteine proteases class.

Enzymes

3325

ubiquitin specific peptidase 1 Show summary »« Hide summary More detailed page go icon to follow link

Target Id

2428

Nomenclature

ubiquitin specific peptidase 1

Previous and unofficial names

deubiquitinating enzyme 1 | ubiquitin carboxyl-terminal hydrolase 1 | ubiquitin specific protease 1 | ubiquitin thioesterase 1 | ubiquitin thiolesterase 1

Genes

USP1 (Hs), Usp1 (Mm), Usp1 (Rn)

Ensembl ID

ENSG00000162607 (Hs), ENSMUSG00000028560 (Mm), ENSRNOG00000007890 (Rn)

UniProtKB AC

O94782 (Hs), Q8BJQ2 (Mm), Q569C3 (Rn)

EC number

3.4.19.12

Selective inhibitors

ML323 pIC₅₀ 7.1 [5]

Selective allosteric modulators

USP1 inhibitor 38-P2 (Inhibition) pIC₅₀ 8.4 [12]

ubiquitin specific peptidase 2 Show summary »« Hide summary More detailed page go icon to follow link

Target Id

2430

Nomenclature

ubiquitin specific peptidase 2

Previous and unofficial names

Genes

USP2 (Hs), Usp2 (Mm), Usp2 (Rn)

Ensembl ID

ENSG00000036672 (Hs), ENSMUSG00000032010 (Mm), ENSRNOG00000006663 (Rn)

UniProtKB AC

O75604 (Hs), O88623 (Mm), Q5U349 (Rn)

EC number

3.4.19.12

Inhibitors

ML364 pK_d 5.3 [3]

ML364 pIC₅₀ 6.0 [3]

Comment

USP2 is a deubiquitinating enzyme that removes ubiquitin from substrate proteins, thus reducing their proteasomal degradation. Inhibiting USP2 would be expected to increase ubiquitination and proteasome-mediated removal of substrate proteins. This mechanism is under investigation in the development of potential broad-spectrum anti-coronavirus (CoV) therapeutics that work by inhibiting USP2's role in ubiquitinating the CoV entry protein ACE2 [3]. In this situation USP2 inhibitors increase ACE2 degradation which reduces the efficiency of ACE2-dependent CoV infection of host cells. USP2 is also an oncology drug target [4,8,13].

ubiquitin specific peptidase 5 Show summary »« Hide summary More detailed page go icon to follow link

Target Id

2431

Nomenclature

ubiquitin specific peptidase 5

Previous and unofficial names

Genes

USP5 (Hs), Usp5 (Mm), Usp5 (Rn)

Ensembl ID

ENSG00000111667 (Hs), ENSMUSG00000038429 (Mm), ENSRNOG00000015409 (Rn)

UniProtKB AC

P45974 (Hs), P56399 (Mm)

EC number

3.4.19.12

ubiquitin specific peptidase 8 Show summary »« Hide summary

Target Id

3209

Nomenclature

ubiquitin specific peptidase 8

Genes

USP8 (Hs), Usp8 (Mm), Usp8 (Rn)

Ensembl ID

ENSG00000138592 (Hs), ENSMUSG00000027363 (Mm), ENSRNOG00000010729 (Rn)

UniProtKB AC

P40818 (Hs)

EC number

3.4.19.12

Inhibitors

compound 61 [PMID: 36221183] pIC₅₀ 9.6 [10]

Comment

USP8 is a deubiquitinating enzyme that is teported to promote both immune evasion and tumourigenesis. Inhibitors of its activity are predicted to provide anti-tumour activity [10].

ubiquitin specific peptidase 14 Show summary »« Hide summary More detailed page go icon to follow link

Target Id

2429

Nomenclature

ubiquitin specific peptidase 14

Previous and unofficial names

Genes

USP14 (Hs), Usp14 (Mm), Usp14 (Rn)

Ensembl ID

ENSG00000101557 (Hs), ENSMUSG00000047879 (Mm), ENSRNOG00000014981 (Rn)

UniProtKB AC

P54578 (Hs), Q9JMA1 (Mm)

EC number

3.4.19.12

Inhibitors

IU1 pIC₅₀ 5.3 [7]

ubiquitin specific peptidase 21 Show summary »« Hide summary

Target Id

3223

Nomenclature

ubiquitin specific peptidase 21

Genes

USP21 (Hs), Usp21 (Mm), Usp21 (Rn)

Ensembl ID

ENSG00000143258 (Hs), ENSMUSG00000053483 (Mm), ENSRNOG00000038347 (Rn)

UniProtKB AC

Q9UK80 (Hs), Q9QZL6 (Mm), B2GUX4 (Rn)

EC number

3.4.19.12

Inhibitors

BAY-805 pIC₅₀ 8.2 [6]

Comment

USP21 is proposed as being involved in procarcinogenic processes [1]. Inhibition of its DUB function is under investigation to reverse its procarcinogenic activity [6].

ubiquitin specific peptidase 28 Show summary »« Hide summary

Target Id

3325

Nomenclature

ubiquitin specific peptidase 28

Previous and unofficial names

ubiquitin specific peptidase 2

Genes

USP28 (Hs), Usp28 (Mm), Usp28 (Rn)

Ensembl ID

ENSG00000048028 (Hs), ENSMUSG00000032267 (Mm), ENSRNOG00000007325 (Rn)

UniProtKB AC

Q96RU2 (Hs), Q5I043 (Mm), D3ZJ96 (Rn)

Inhibitors

CAS-010 pIC₅₀ 8.7 [2]

USP28 inhibitor 9p pIC₅₀ 7.4 [14]

CT1113 pIC₅₀ >7.0 [9]

Comment

USP28 is overexpressed in many types of cancer [11]. USP28 is closely related to USP25 and some inhibitors (e.g. CT1113) are not selective. The development of selective inhibitors is ongoing.

References

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1. An T, Lu Y, Yan X, Hou J. (2022) Insights Into the Properties, Biological Functions, and Regulation of USP21. Front Pharmacol, 13: 944089. [PMID:35846989]

2. Bratt AS, Kilgas S, Guzman MIT, Magin RS, Maisonet IJ, Starnbach CA, Teh WP, Varca AC, Hu B, Guzman ET. (2025) Pharmacologic interrogation of USP28 cellular function in p53 signaling. Cell Chem Biol, Epub ahead of print. DOI: 10.1016/j.chembiol.2025.08.002

3. Dang F, Bai L, Dong J, Hu X, Wang J, Paulo JA, Xiong Y, Liang X, Sun Y, Chen Y et al.. (2023) USP2 inhibition prevents infection with ACE2-dependent coronaviruses in vitro and is protective against SARS-CoV-2 in mice. Sci Transl Med, 15 (725): eadh7668. [PMID:38055802]

4. Davis MI, Pragani R, Fox JT, Shen M, Parmar K, Gaudiano EF, Liu L, Tanega C, McGee L, Hall MD et al.. (2016) Small Molecule Inhibition of the Ubiquitin-specific Protease USP2 Accelerates cyclin D1 Degradation and Leads to Cell Cycle Arrest in Colorectal Cancer and Mantle Cell Lymphoma Models. J Biol Chem, 291 (47): 24628-24640. [PMID:27681596]

5. Dexheimer TS, Rosenthal AS, Luci DK, Liang Q, Villamil MA, Chen J, Sun H, Kerns EH, Simeonov A, Jadhav A et al.. (2014) Synthesis and Structure-Activity Relationship Studies of N-Benzyl-2-phenylpyrimidin-4-amine Derivatives as Potent USP1/UAF1 Deubiquitinase Inhibitors with Anticancer Activity against Nonsmall Cell Lung Cancer. J Med Chem, 57 (19): 8099-110. [PMID:25229643]

6. Göricke F, Vu V, Smith L, Scheib U, Böhm R, Akkilic N, Wohlfahrt G, Weiske J, Bömer U, Brzezinka K et al.. (2023) Discovery and Characterization of BAY-805, a Potent and Selective Inhibitor of Ubiquitin-Specific Protease USP21. J Med Chem, 66 (5): 3431-3447. [PMID:36802665]

7. Lee BH, Lee MJ, Park S, Oh DC, Elsasser S, Chen PC, Gartner C, Dimova N, Hanna J, Gygi SP et al.. (2010) Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature, 467 (7312): 179-84. [PMID:20829789]

8. Lee TG, Woo SM, Seo SU, Kim S, Park JW, Chang YC, Kwon TK. (2023) Inhibition of USP2 Enhances TRAIL-Mediated Cancer Cell Death through Downregulation of Survivin. Int J Mol Sci, 24 (16). [PMID:37628997]

9. Peng J, Jiang K, Bu J, Wang F. (2020) Ubiquitin-specific protease inhibitors, and preparation method therefor and application thereof. Patent number: WO2020224652A1. Assignee: Chaser Therapeutics Inc. Priority date: 08/05/2020. Publication date: 12/11/2020.

10. Tan L, Shan H, Han C, Zhang Z, Shen J, Zhang X, Xiang H, Lu K, Qi C, Li Y et al.. (2022) Discovery of Potent OTUB1/USP8 Dual Inhibitors Targeting Proteostasis in Non-Small-Cell Lung Cancer. J Med Chem, 65 (20): 13645-13659. [PMID:36221183]

11. Wang X, Liu Z, Zhang L, Yang Z, Chen X, Luo J, Zhou Z, Mei X, Yu X, Shao Z et al.. (2018) Targeting deubiquitinase USP28 for cancer therapy. Cell Death Dis, 9 (2): 186. [PMID:29415985]

12. Zhang J, Liu B, Ren R, Song S, Bao X, Huan X, Li H, Xu J, Yu T, Wang R et al.. (2025) Discovery and Optimization of a Series of Novel Morpholine-Containing USP1 Inhibitors. J Med Chem, [Epub ahead of print]. [PMID:39902599]

13. Zhang S, Guo Y, Zhang S, Wang Z, Zhang Y, Zuo S. (2023) Targeting the deubiquitinase USP2 for malignant tumor therapy (Review). Oncol Rep, 50 (4). [PMID:37594087]

14. Zhou D, Xu Z, Huang Y, Wang H, Zhu X, Zhang W, Song W, Gao T, Liu T, Wang M et al.. (2023) Structure-based discovery of potent USP28 inhibitors derived from Vismodegib. Eur J Med Chem, 254: 115369. [PMID:37075624]

How to cite this family page

Database page citation:

C19: Ubiquitin-specific protease. Accessed on 11/09/2025. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=730.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Fabbro D, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Enzymes. Br J Pharmacol. 180 Suppl 2:S289-373.