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A Review on Targeted Protein Degradation and Its Novel Therapeutic Approaches

Nilesh s Pendbhaje, Ashwini A. Jamdhade, Shain M. Pathan, Rupali V. Nirmal

Abstract


A new concept of drug development is drug-induced degradation of a target protein. Protein degradation is one of the cell's methods for permanently inactivating proteins. The Ubiquitin-Proteasome System (UPS) and autophagy are two main intracellular protein degradation pathways in eukaryotes. Autophagy has been shown to be induced by inhibiting proteasomal activities, suggesting a coordinated and complementary relationship between these two mechanisms. However, little is known about autophagy's function in UPS control. Various targeted protein degradation pathways, such as PROTACs, Degradation TAG System, Auxin inducible degron, DeGraff and ZIF1 proteolytic systems, and therapeutic approaches based on protein degradation, have been shown in this study. We have also addressed PROTACS, which target cancer-related targets for cancer therapy, in this study.


 


Keywords


Targeted protein degradation, Ubiquitin-proteasome system, PROTACs, Autophagylysosome system, Therapeutic approaches, Anticancer

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References


Daniels Danette L, Riching Kristin M, Marjeta Urh. Targeted protein degradation: A new direction for treatment of diseases. Health & Medicine, Research Outreach. 326p.

Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem. 1998; 67: 425–79.

Voges D, Zwickl P, Baumeister W. The 26S proteasome: a molecular machine designed for controlled proteolysis. Annu Rev Biochem. 1999; 68: 1015–68.

Kathleen Miho Sakamoto. Targeting proteins for ubiquitination and degradation in the treatment of human disease. Dissertation (Ph.D.), California Institute of Technology. 2003.

Wang XJ, Yu J, Wong Sunny H, Cheng Alfred SL, Chan Francis KL, Ng Simon SM, Cho Chi H, Sung Joseph JY, Wu William KK. A novel crosstalk between two major protein degradation systems Regulation of proteasomal activity by autophagy. Autophagy (Taylor and francis). Oct 2013; 9(10): 1500–1508.

Salami J, Crews CM. Waste disposal-An attractive strategy for cancer therapy. Science (New York, NY). 2017; 355(6330): 1163–1167.

Klaips CL, Jayaraj GG, Hartl FU. Pathways of cellular proteostasis in aging and disease. J cell biol. 2018; 217(1): 51–63.

Hoeller D, Dikic I. Targeting the ubiquitin system in cancer therapy. Nature. 2009; 458(7237): 438–444.

Galluzzi L, Bravo-San Pedro JM, Levine B, Green DR, Kroemer G. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat Rev Drug Discov. 2017; 16(7): 487–511.

Mayor-Ruiz C, Winter GE. Identification and characterization of cancer vulnerabilities via targeted protein degradation. Drug Discov Today Technol. 2019; 31: 81–90.

Barghout Samir H. Targeted Protein Degradation: An Emerging Therapeutic Strategy in Cancer. Anti-Cancer Agents Med Chem (Formerly, Current Medicinal Chemistry-Anti-Cancer Agents). Apr 2020.

Hai Qiu Wu, David Baker, Huib Ovaa. Small molecules that target the ubiquitin system. Biochem Soc Trans. 2020; 48: 479–497.

John Hanna, Angel Guerra-Moreno, Jessie Ang, Yagmur Micoogullari. REVIEW Protein Degradation and the Pathologic Basis of Disease. American Society for Investigative Pathology (ASIP). Jan 2019; 189(01): 94–103. http://ajp.amjpathol.org/

Wu WK, Sakamoto KM, Milani M, Aldana Masankgay G, Fan D, Wu K, et al. Macroautophagy modulates cellular response to proteasome inhibitors in cancer therapy. Drug Resist Updat. 2010; 13(3): 87–92. PMID: 20462785; http://dx.doi.org/10.1016/j. drup.2010.04.003

Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem. 2007; 282(33): 24131–45; PMID: 17580304; http://dx.doi. org/10.1074/jbc. M702824200

Kirkin V, Lamark T, Sou YS, Bjørkøy G, Nunn JL, Bruun JA, et al. A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol Cell. 2009; 33(4): 505–16. PMID: 19250911; http://dx.doi. org/10.1016/j.molcel.2009.01.020

Milani M, Rzymski T, Mellor HR, Pike L, Bottini A, Generali D, et al. The role of ATF4 stabilization and autophagy in resistance of breast cancer cells treated with Bortezomib. Cancer Res. 2009; 69(10): 4415–23. PMID: 19417138; http://dx.doi.org/10.1158/0008-5472.CAN-08-2839

Pandey UB, Nie Z, Batlevi Y, McCray BA, Ritson GP, Nedelsky NB, et al. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature. 2007; 447(7146): 859–63. PMID: 17568747; http://dx.doi. org/10.1038/nature05853

Wu WK, Cho CH, Lee CW, Wu YC, Yu L, Li ZJ, et al. Macroautophagy and ERK phosphorylation counteract the antiproliferative effect of proteasome inhibitor in gastric cancer cells. Autophagy. 2010; 6(2): 228–38. PMID: 20087064; http://dx.doi. org/10.4161/auto. 6.2.11042

Pandey UB, Batlevi Y, Baehrecke EH, Taylor JP. HDAC6 at the intersection of autophagy, the ubiquitin-proteasome system and neurodegeneration. Autophagy. 2007; 3(6): 643–5. PMID:17912024

Ian Collins, Hannah Wang, Caldwell John J, Raj Chopra. Chemical approaches to targeted protein degradation through modulation of the ubiquitin–proteasome pathway. Biochemical Journal. 2017; 474(7): 1127–1147.

Korolchuk VI, Menzies FM, Rubinsztein DC. Mechanisms of cross-talk between the ubiquitin-proteasome and autophagy-lysosome systems. FEBS Lett. 2010; 584(7): 1393–1398.

Moon S, Lee B-H. Chemically induced cellular proteolysis: an emerging therapeutic strategy for undruggable targets. Mol Cells. 2018; 41(11): 933–942. https://doi.org/10.14348/molcells. 2018.0372

Wang S, Han L, Han J, Li P, Ding Q, Zhang Q-J, et al. Uncoupling of PARP1 trapping and inhibition using selective PARP1 degradation. Nat Chem Biol. 2019; 15(12): 1223–1231. https://doi.org/10.1038/s41589-019-0379-2

Okuhira K, Ohoka N, Sai K, Nishimaki-Mogami T, Itoh Y, Ishikawa M, et al. Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein. FEBS Lett. 2011; 585(8): 1147–1152. https://doi. org/10.1016/j.febslet. 2011.03.019

Ohoka N, Okuhira K, Ito M, Nagai K, Shibata N, Hattori T, et al. In vivo knockdown of pathogenic proteins via specific and nongenetic inhibitor of apoptosis protein (IAP)-dependent protein erasers (SNIPERs). J Biol Chem. 2017; 292(11): 4556–4570. https://doi.org/ 10.1074/jbc.M116.768853

Daniels Danette L, Riching Kristin M, Marjeta Urh. Targeted protein degradation: A new direction for treatment of diseases. Health & Medicine Articles, Research Outreach. - Page 3 of 26 -

Pooja Gopal, Thomas Dick. Targeted protein degradation in antibacterial drug discovery? Prog Biophys Mol Biol. 2020; 152: 10–14.

Neklesa Taavi K, Winkler James D, Crews Craig M. Targeted protein degradation by PROTACs. Pharmacol Ther. 2017; 174: 138–144.

EBioMedicine. Targeted Protein Degradation: Unlocking the Therapeutic Proteome. EBioMedicine. 2018; 30: 1–2. https://doi.org/10.1016/j.ebiom.2018.04.003 2352-3964/2018

Xiuyun Sun, Hongying Gao, Yiqing Yang, Ming He, Yue Wu, Yugang Song, Yan Tong, Yu Rao. PROTACs: great opportunities for academia and industry. Signal Transduct Target Ther. 2019; 4: 64.

International Application Published under the Patent Cooperation Treaty (PCT). World Intellectual Property Organization International Bureau; International Publication Date 5 Jan 2012 (05.01.2012). International Publication Number-WO 2012/003281 A2.

Neklesa TK, Tae HS, Schneekloth AR, Stulberg MJ, Corson TW, Sundberg TB, et al. Small-molecule hydrophobic tagging-induced degradation of HaloTag fusion proteins. Nat Chem Biol. 2011; 7(8): 538–543. doi:10.1038/nchembio.597

Yuri Prozzillo, Gaia Fattorini, Maria Virginia Santopietro, Luigi Suglia, Alessandra Ruggiero, Diego Ferreri, Giovanni Messina. Review: Targeted Protein Degradation Tools: Overview and Future Perspectives. Biology. 2020; 9(12): 421.

Erb MA, Scott TG, Li BE, Xie H, Paulk J, Seo HS, Souza A, Roberts JM, Dastjerdi S, Buckley DL, et al. Transcription control by the ENL YEATS domain in acute leukaemia. Nature. 2017; 543(7644): 270–274.

Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer. 2004; 4(4): 314–322.

Raje N, Anderson K. Thalidomide: a revival story. New Engl J Med. 1999; 341(21): 1606–1609.

Nishimura K, Fukagawa T, Takisawa H, et al. Anauxin based degron system for the rapid depletion of proteins in nonplant cells. Nat Methods. 2009; 6(12): 917–922. https://doi.org/ 10.1038/nmeth.1401

Sascha Roth, Fulcher Luke J, Sapkota Gopal P. Advances in targeted degradation of endogenous proteins. Cell Mol Life Sci. 2019; 76(14): 2761–2777.

Wang S, Tang NH, Lara-Gonzalez P, et al. A toolkit for GFP-mediated tissue-specifc protein degradation in C. elegans. Development. 2017; 144(14): 2694–2701. https://doi.org/ 10.1242/dev.15009

Caussinus E, Kanca O, Afolter M. Fluorescent fusion protein knockout mediated by anti-GFP nanobody. Nat Struct Mol Biol. 2012; 19(1): 117–121. https://doi.org/10.1038/nsmb.2180

Pranam Chatterjee, Manvitha Ponnapati, Christian Kramme, Plesa Alexander M, Church George M, Jacobson Joseph M. Targeted Intracellular Degradation of SARS-CoV-2 2 via Computationally-Optimized Peptide Fusions. Commun Biol. 2020; 3: 715.

Abbott TR, et al. Development of CRISPR as an antiviral strategy to combat 305 SARS-CoV-2 and influenza. Cell. 2020; 181(4): 865–876.e12.

Lino CA, Harper JC, Carney JP, Timlin JA. Delivering CRISPR: a review 307 of the challenges and approaches. Drug Deliv. 2018; 25(1): 1234–1257.

Mélissanne de Wispelaere, Guangyan Du, Donovan Katherine A, Tinghu Zhang, Eleuteri Nicholas A, Yuan Jingting C, Joann Kalabathula, Nowak Radosław P, Fischer Eric S, Gray Nathanael S, Yang Priscilla L. Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations. Nat Commun. 2019; 10(1): 3468. https://doi.org/10.1038/ s41467-019-11429-w

Guerra-Moreno A, Isasa M, Bhanu MK, Waterman DP, Eapen VV, Gygi SP, Hanna J. Proteomic analysis identifies ribosome reduction as an effective proteotoxic stress response. J Biol Chem. 2015; 290(50): 29695–29706.

Kogan SC. Medicine: poisonous contacts. Science. 2010; 328(5975): 184–185.

Zhang XW, Yan XJ, Zhou ZR, Yang FF, Wu ZY, Sun HB, Liang WX, Song AX, Lallemand-Breitenbach V, Jeanne M, Zhang QY, Yang HY, Huang QH, Zhou GB, Tong JH, Zhang Y, Wu JH, Hu HY, de Thé H, Chen SJ, Chen Z. Arsenic trioxide controls the fate of the PML-RARalphaonco protein by directly binding PML. Science. 2010; 328(5975): 240–243.

deThé H, Pandolfi PP, Chen Z. Acute promyelocyticleukemia: a paradigm for oncoprotein-targeted cure. Cancer Cell. 2017; 32(5): 552–560.

Belshaw PJ, Ho SN, Crabtree GR, Schreiber SL. Controlling protein association and subcellular localization with a synthetic ligand that induces heterodimerization of proteins. Proc Natl Acad Sci USA. 1996; 93(10): 4604–7.

Chen Z, Hagler J, Palombella VJ, Melandri F, Scherer D, Ballard D, Maniatis T. Signal-induced site-specific phosphorylation targets IKB x to the ubiquitin-proteasome pathway. Genes Dev. 1995; 9: 1586–97.

Deng L, Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C, Chen ZJ. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell. 2000; 103(2): 351–61.

Zhao B, Burgess K. PROTACs suppression of CDK4/6, crucial kinases for cell cycle regulation in cancer. Chem Commun. 2019; 55(18): 2704–2707.


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