The Present and Future of Novel Protein Degradation Technology

Author(s): Liwen Xia, Wei Liu, Yinsen Song, Hailiang Zhu*, Yongtao Duan*

Journal Name: Current Topics in Medicinal Chemistry

Volume 19 , Issue 20 , 2019

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Proteolysis targeting chimeras (PROTACs), as a novel therapeutic modality, play a vital role in drug discovery. Each PROTAC contains three key parts; a protein-of-interest (POI) ligand, a E3 ligase ligand, and a linker. These bifunctional molecules could mediate the degradation of POIs by hijacking the activity of E3 ubiquitin ligases for POI ubiquitination and subsequent degradation via the ubiquitin proteasome system (UPS). With several advantages over other therapeutic strategies, PROTACs have set off a new upsurge of drug discovery in recent years. ENDTAC, as the development of PROTACs technology, is now receiving more attention. In this review, we aim to summarize the rapid progress from 2018 to 2019 in protein degradation and analyze the challenges and future direction that need to be addressed in order to efficiently develop potent protein degradation technology.

Keywords: PROTACs, ENDTAC, degradation, progress, challenges, UPS.

Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[] [PMID: 30207593]
Deng, X.; Nakamura, Y. Cancer precision medicine: from cancer screening to drug selection and personalized immunotherapy. Trends Pharmacol. Sci., 2017, 38(1), 15-24.
[] [PMID: 27842888]
Meeusen, E.; Lim, E.; Mathivanan, S. Secreted tumor antigens - immune biomarkers for diagnosis and therapy. Proteomics, 2017, 17(23-24)1600442
[] [PMID: 28714192]
Duan, Y.T.; Sangani, C.B.; Liu, W.; Soni, K.V.; Yao, Y. New promises to cure cancer and other genetic diseases/disorders: epi-drugs through epigenetics. Curr. Top. Med. Chem., 2019, 19(12), 972-994.
[] [PMID: 31161992]
Valeur, E.; Jimonet, P. New Modalities, Technologies, and Partnerships in Probe and Lead Generation: Enabling a Mode-of-Action Centric Paradigm. J. Med. Chem., 2018, 61(20), 9004-9029.
[] [PMID: 29851477]
Wu, T.; Dai, Y. Tumor microenvironment and therapeutic response. Cancer Lett., 2017, 387, 61-68.
[] [PMID: 26845449]
Collins, F.S.; Varmus, H. A new initiative on precision medicine. N. Engl. J. Med., 2015, 372(9), 793-795.
[] [PMID: 25635347]
Syn, N.L.; Teng, M.W.L.; Mok, T.S.K.; Soo, R.A. De-novo and acquired resistance to immune checkpoint targeting. Lancet Oncol., 2017, 18(12), e731-e741.
[] [PMID: 29208439]
Turley, S.J.; Cremasco, V.; Astarita, J.L. Immunological hallmarks of stromal cells in the tumour microenvironment. Nat. Rev. Immunol., 2015, 15(11), 669-682.
[] [PMID: 26471778]
Kaczmarek, J.C.; Kowalski, P.S.; Anderson, D.G. Advances in the delivery of RNA therapeutics: from concept to clinical reality. Genome Med., 2017, 9(1), 60.
[] [PMID: 28655327]
Aronson, S.J.; Rehm, H.L. Building the foundation for genomics in precision medicine. Nature, 2015, 526(7573), 336-342.
[] [PMID: 26469044]
Xiao-Jie, L.; Hui-Ying, X.; Zun-Ping, K.; Jin-Lian, C.; Li-Juan, J. CRISPR-Cas9: a new and promising player in gene therapy. J. Med. Genet., 2015, 52(5), 289-296.
[] [PMID: 25713109]
Pettersson, M.; Crews, C.M. PROteolysis TArgeting Chimeras (PROTACs) - Past, present and future. Drug Discov. Today. Technol., 2019, 31, 15-27.
[] [PMID: 31200855]
Wang, P.; Zhou, J. Proteolysis Targeting Chimera (PROTAC): A Paradigm-Shifting Approach in Small Molecule Drug Discovery. Curr. Top. Med. Chem., 2018, 18(16), 1354-1356.
[] [PMID: 30306871]
Duan, Y.; Liu, W.; Tian, L.; Mao, Y.; Song, C. Targeting tubulin-colchicine site for cancer therapy: inhibitors, antibody-drug conjugates and degraders. Curr. Top. Med. Chem., 2019, 19(15), 1289-1304. Epub ahead of print
[] [PMID: 31210108]
Gadd, M.S.; Testa, A.; Lucas, X.; Chan, K-H.; Chen, W.; Lamont, D.J.; Zengerle, M.; Ciulli, A. Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat. Chem. Biol., 2017, 13(5), 514-521.
[] [PMID: 28288108]
Edmondson, S.D.; Yang, B.; Fallan, C. Proteolysis targeting chimeras (PROTACs) in ‘beyond rule-of-five’ chemical space: Recent progress and future challenges. Bioorg. Med. Chem. Lett., 2019, 29(13), 1555-1564.
[] [PMID: 31047748]
Lebraud, H.; Wright, D.J.; Johnson, C.N.; Heightman, T.D. Protein degradation by in-cell self-assembly of proteolysis targeting chimeras. ACS Cent. Sci., 2016, 2(12), 927-934.
[] [PMID: 28058282]
Schneekloth, A.R.; Pucheault, M.; Tae, H.S.; Crews, C.M. Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics. Bioorg. Med. Chem. Lett., 2008, 18(22), 5904-5908.
[] [PMID: 18752944]
Dueber, E.C.; Schoeffler, A.J.; Lingel, A.; Elliott, J.M.; Fedorova, A.V.; Giannetti, A.M.; Zobel, K.; Maurer, B.; Varfolomeev, E.; Wu, P.; Wallweber, H.J.; Hymowitz, S.G.; Deshayes, K.; Vucic, D.; Fairbrother, W.J. Antagonists induce a conformational change in cIAP1 that promotes autoubiquitination. Science, 2011, 334(6054), 376-380.
[] [PMID: 22021857]
Watt, G.F.; Scott-Stevens, P.; Gaohua, L. Targeted protein degradation in vivo with proteolysis targeting chimeras: current status and future considerations. Drug Discov. Today. Technol., 2019, 31, 69-80.
[] [PMID: 31200862]
Mager, D.E. Target-mediated drug disposition and dynamics. Biochem. Pharmacol., 2006, 72(1), 1-10.
[] [PMID: 16469301]
Zhang, X.; Lee, H.C.; Shirazi, F.; Baladandayuthapani, V.; Lin, H.; Kuiatse, I.; Wang, H.; Jones, R.J.; Berkova, Z.; Singh, R.K.; Lu, J.; Qian, Y.; Raina, K.; Coleman, K.G.; Crews, C.M.; Li, B.; Wang, H.; Hailemichael, Y.; Thomas, S.K.; Wang, Z.; Davis, R.E.; Orlowski, R.Z. Protein targeting chimeric molecules specific for bromodomain and extra-terminal motif family proteins are active against pre-clinical models of multiple myeloma. Leukemia, 2018, 32(10), 2224-2239.
[] [PMID: 29581547]
Bondeson, D.P.; Mares, A.; Smith, I.E.D.; Ko, E.; Campos, S.; Miah, A.H.; Mulholland, K.E.; Routly, N.; Buckley, D.L.; Gustafson, J.L.; Zinn, N.; Grandi, P.; Shimamura, S.; Bergamini, G.; Faelth-Savitski, M.; Bantscheff, M.; Cox, C.; Gordon, D.A.; Willard, R.R.; Flanagan, J.J.; Casillas, L.N.; Votta, B.J.; den Besten, W.; Famm, K.; Kruidenier, L.; Carter, P.S.; Harling, J.D.; Churcher, I.; Crews, C.M. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat. Chem. Biol., 2015, 11(8), 611-617.
[] [PMID: 26075522]
Winter, G.E.; Buckley, D.L.; Paulk, J.; Roberts, J.M.; Souza, A.; Dhe-Paganon, S.; Bradner, J.E. Drug development. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science, 2015, 348(6241), 1376-1381.
[] [PMID: 25999370]
Kargbo, R.B. Treatment of prostate cancers and Kennedy’s disease by PROTAC-androgen receptor degradation. ACS Med. Chem. Lett., 2019, 10(5), 701-702.
[] [PMID: 31097985]
Gabrielsson, J.; Fjellström, O.; Ulander, J.; Rowley, M.; Van Der Graaf, P.H. Pharmacodynamic-pharmacokinetic integration as a guide to medicinal chemistry. Curr. Top. Med. Chem., 2011, 11(4), 404-418.
[] [PMID: 21320067]
Morgan, P.; Van Der Graaf, P.H.; Arrowsmith, J.; Feltner, D.E.; Drummond, K.S.; Wegner, C.D.; Street, S.D. Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival. Drug Discov. Today, 2012, 17(9-10), 419-424.
[] [PMID: 22227532]
Davoine, F.; Lacy, P. Eosinophil cytokines, chemokines, and growth factors: emerging roles in immunity. Front. Immunol., 2014, 5, 570.
[] [PMID: 25426119]
Majka, M.; Janowska-Wieczorek, A.; Ratajczak, J.; Ehrenman, K.; Pietrzkowski, Z.; Kowalska, M.A. Numerous growth factors, cytokines, and chemokines are secreted by human CD34(+) cells, myeloblasts, erythroblasts, and megakaryoblasts and regulate normal hematopoiesis in an autocrine/paracrine manner. Blood, 2001, 97(10), 3075-3085.
Patel, D.; Lahiji, A.; Patel, S.; Franklin, M.; Jimenez, X.; Hicklin, D.J.; Kang, X. Monoclonal antibody cetuximab binds to and down-regulates constitutively activated epidermal growth factor receptor vIII on the cell surface. Anticancer Res., 2007, 27(5A), 3355-3366.
[PMID: 17970081]
Tiseo, M.; Bartolotti, M.; Gelsomino, F.; Bordi, P. Emerging role of gefitinib in the treatment of non-small-cell lung cancer (NSCLC). Drug Des. Devel. Ther., 2010, 4, 81-98.
[] [PMID: 20531963]
Nalawansha, D.A.; Paiva, S-L.; Rafizadeh, D.N.; Pettersson, M.; Qin, L.; Crews, C.M. Targeted protein internalization and degradation by endosome targeting chimeras (ENDTACs). ACS Cent. Sci., 2019, 5(6), 1079-1084.
[] [PMID: 31263767]

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Article Details

Year: 2019
Page: [1784 - 1788]
Pages: 5
DOI: 10.2174/1568026619666191011162955

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