Emerging Drug Development Technologies Targeting Ubiquitination for Cancer Therapeutics

Overview

Journal Pharmacol Ther

Specialty Pharmacology

Date 2019 Mar 10

PMID 30851297

Citations 33

Authors

Gianluca Veggiani

Maria Carla Rosales Gerpe

Sachdev S Sidhu

Wei Zhang

Affiliations

Soon will be listed here.

Abstract

Development of effective cancer therapeutic strategies relies on our ability to interfere with cellular processes that are dysregulated in tumors. Given the essential role of the ubiquitin proteasome system (UPS) in regulating a myriad of cellular processes, it is not surprising that malfunction of UPS components is implicated in numerous human diseases, including many types of cancer. The clinical success of proteasome inhibitors in treating multiple myeloma has further stimulated enthusiasm for targeting UPS proteins for pharmacological intervention in cancer treatment, particularly in the precision medicine era. Unfortunately, despite tremendous efforts, the paucity of potent and selective UPS inhibitors has severely hampered attempts to exploit the UPS for therapeutic benefits. To tackle this problem, many groups have been working on technology advancement to rapidly and effectively screen for potent and specific UPS modulators as intracellular probes or early-phase therapeutic agents. Here, we review several emerging technologies for developing chemical- and protein-based molecules to manipulate UPS enzymatic activity, with the aim of providing an overview of strategies available to target ubiquitination for cancer therapy.

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References

Gavory G, ODowd C, Helm M, Flasz J, Arkoudis E, Dossang A . Discovery and characterization of highly potent and selective allosteric USP7 inhibitors. Nat Chem Biol. 2017; 14(2):118-125. DOI: 10.1038/nchembio.2528. View

Landry Y, Gies J . Drugs and their molecular targets: an updated overview. Fundam Clin Pharmacol. 2008; 22(1):1-18. DOI: 10.1111/j.1472-8206.2007.00548.x. View

Wang X, Mazurkiewicz M, Hillert E, Olofsson M, Pierrou S, Hillertz P . The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells. Sci Rep. 2016; 6:26979. PMC: 4893612. DOI: 10.1038/srep26979. View

Keseru G, Makara G . The influence of lead discovery strategies on the properties of drug candidates. Nat Rev Drug Discov. 2009; 8(3):203-12. DOI: 10.1038/nrd2796. View

Franzini R, Biendl S, Mikutis G, Samain F, Scheuermann J, Neri D . "Cap-and-Catch" Purification for Enhancing the Quality of Libraries of DNA Conjugates. ACS Comb Sci. 2015; 17(7):393-8. DOI: 10.1021/acscombsci.5b00072. View

Pozhidaeva A, Valles G, Wang F, Wu J, Sterner D, Nguyen P . USP7-Specific Inhibitors Target and Modify the Enzyme's Active Site via Distinct Chemical Mechanisms. Cell Chem Biol. 2017; 24(12):1501-1512.e5. DOI: 10.1016/j.chembiol.2017.09.004. View

Maynard J, Chen G, Georgiou G, Iverson B . In vitro scanning-saturation mutagenesis. Methods Mol Biol. 2002; 182:149-63. DOI: 10.1385/1-59259-194-9:149. View

Renatus M, Parrado S, DArcy A, Eidhoff U, Gerhartz B, Hassiepen U . Structural basis of ubiquitin recognition by the deubiquitinating protease USP2. Structure. 2006; 14(8):1293-302. PMC: 7126176. DOI: 10.1016/j.str.2006.06.012. View

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

10.

VanDemark A, Hill C . Structural basis of ubiquitylation. Curr Opin Struct Biol. 2002; 12(6):822-30. DOI: 10.1016/s0959-440x(02)00389-5. View

11.

Dixon S, Stockwell B . Identifying druggable disease-modifying gene products. Curr Opin Chem Biol. 2009; 13(5-6):549-55. PMC: 2787993. DOI: 10.1016/j.cbpa.2009.08.003. View

12.

Darwin K, Ehrt S, Gutierrez-Ramos J, Weich N, Nathan C . The proteasome of Mycobacterium tuberculosis is required for resistance to nitric oxide. Science. 2003; 302(5652):1963-6. DOI: 10.1126/science.1091176. View

13.

Litovchick A, Dumelin C, Habeshian S, Gikunju D, Guie M, Centrella P . Encoded Library Synthesis Using Chemical Ligation and the Discovery of sEH Inhibitors from a 334-Million Member Library. Sci Rep. 2015; 5:10916. PMC: 4603778. DOI: 10.1038/srep10916. View

14.

Shen M, Schmitt S, Buac D, Dou Q . Targeting the ubiquitin-proteasome system for cancer therapy. Expert Opin Ther Targets. 2013; 17(9):1091-108. PMC: 3773690. DOI: 10.1517/14728222.2013.815728. View

15.

Bishop P, Rocca D, Henley J . Ubiquitin C-terminal hydrolase L1 (UCH-L1): structure, distribution and roles in brain function and dysfunction. Biochem J. 2016; 473(16):2453-62. PMC: 4980807. DOI: 10.1042/BCJ20160082. View

16.

Mulder L, Harari A, Simon V . Cytidine deamination induced HIV-1 drug resistance. Proc Natl Acad Sci U S A. 2008; 105(14):5501-6. PMC: 2291111. DOI: 10.1073/pnas.0710190105. View

17.

Fraczek M, Naseeb S, Delneri D . History of genome editing in yeast. Yeast. 2018; 35(5):361-368. PMC: 5969250. DOI: 10.1002/yea.3308. View

18.

Canny M, Moatti N, Wan L, Fradet-Turcotte A, Krasner D, Mateos-Gomez P . Inhibition of 53BP1 favors homology-dependent DNA repair and increases CRISPR-Cas9 genome-editing efficiency. Nat Biotechnol. 2017; 36(1):95-102. PMC: 5762392. DOI: 10.1038/nbt.4021. View

19.

Turnbull A, Ioannidis S, Krajewski W, Pinto-Fernandez A, Heride C, Martin A . Molecular basis of USP7 inhibition by selective small-molecule inhibitors. Nature. 2017; 550(7677):481-486. PMC: 6029662. DOI: 10.1038/nature24451. View

20.

Leung I, Dekel A, Shifman J, Sidhu S . Saturation scanning of ubiquitin variants reveals a common hot spot for binding to USP2 and USP21. Proc Natl Acad Sci U S A. 2016; 113(31):8705-10. PMC: 4978272. DOI: 10.1073/pnas.1524648113. View