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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Hydrophobic Tag Tethering Degradation, The Emerging Targeted Protein Degradation Strategy

Author(s): Jieke Gao, Jiantao Zhang, Xiaoli Han and Jinming Zhou*

Volume 30, Issue 27, 2023

Published on: 14 November, 2022

Page: [3137 - 3155] Pages: 19

DOI: 10.2174/0929867329666220930120328

Price: $65

Abstract

Targeted protein degradation (TPD) strategies have become a new trend in drug discovery due to the capability of triggering the degradation of protein of interest (POI) selectively and effectively in recent decades. Particularly, the hydrophobic tag tethering degrader (HyTTD) has drawn a lot of attention and may offer a promising strategy for new drug research and development in the future. Herein, we will give an overview of the development of HyTTD, the structure-activity relationship (SAR) between HyTTD and linkers, HyTs, and ligand motifs, as well as the various HyTTDs targeting different targets, thus offering a rational strategy for the design of HyTTDs in further TPD drug discovery.

Keywords: Targeted protein degradation, hydrophobic tag tethering degrader, hydrophobic tag, drug discovery, structure-activity relationship, HyTTDs.

« Previous
[1]
Li, H.; Dong, J.; Cai, M.; Xu, Z.; Cheng, X.D.; Qin, J.J. Protein degradation technology: A strategic paradigm shift in drug discovery. J. Hematol. Oncol., 2021, 14(1), 138.
[http://dx.doi.org/10.1186/s13045-021-01146-7] [PMID: 34488823]
[2]
Hopkins, A.L.; Groom, C.R. The druggable genome. Nat. Rev. Drug Discov., 2002, 1(9), 727-730.
[http://dx.doi.org/10.1038/nrd892] [PMID: 12209152]
[3]
Lai, A.C.; Crews, C.M. Induced protein degradation: An emerging drug discovery paradigm. Nat. Rev. Drug Discov., 2017, 16(2), 101-114.
[http://dx.doi.org/10.1038/nrd.2016.211] [PMID: 27885283]
[4]
Sun, X.; Gao, H.; Yang, Y.; He, M.; Wu, Y.; Song, Y.; Tong, Y.; Rao, Y. PROTACs: Great opportunities for academia and industry. Signal Transduct. Target. Ther., 2019, 4(1), 64.
[http://dx.doi.org/10.1038/s41392-019-0101-6] [PMID: 31885879]
[5]
Békés, M.; Langley, D.R.; Crews, C.M. PROTAC targeted protein degraders: The past is prologue. Nat. Rev. Drug Discov., 2022, 21(3), 181-200.
[http://dx.doi.org/10.1038/s41573-021-00371-6] [PMID: 35042991]
[6]
Khan, S.; He, Y.; Zhang, X.; Yuan, Y.; Pu, S.; Kong, Q.; Zheng, G.; Zhou, D. PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics. Oncogene, 2020, 39(26), 4909-4924.
[http://dx.doi.org/10.1038/s41388-020-1336-y] [PMID: 32475992]
[7]
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.
[http://dx.doi.org/10.1038/nchembio.1858] [PMID: 26075522]
[8]
Caianiello, D.F.; Zhang, M.; Ray, J.D.; Howell, R.A.; Swartzel, J.C.; Branham, E.M.J.; Chirkin, E.; Sabbasani, V.R.; Gong, A.Z.; McDonald, D.M.; Muthusamy, V.; Spiegel, D.A. Bifunctional small molecules that mediate the degradation of extracellular proteins. Nat. Chem. Biol., 2021, 17(9), 947-953.
[http://dx.doi.org/10.1038/s41589-021-00851-1] [PMID: 34413525]
[9]
Banik, S.M.; Pedram, K.; Wisnovsky, S.; Ahn, G.; Riley, N.M.; Bertozzi, C.R. Lysosome-targeting chimaeras for degradation of extracellular proteins. Nature, 2020, 584(7820), 291-297.
[http://dx.doi.org/10.1038/s41586-020-2545-9] [PMID: 32728216]
[10]
Takahashi, D.; Moriyama, J.; Nakamura, T.; Miki, E.; Takahashi, E.; Sato, A.; Akaike, T.; Itto-Nakama, K.; Arimoto, H. AUTACs: Cargo-specific degraders using selective autophagy. Mol. Cell, 2019, 76(5), 797-810.e10.
[http://dx.doi.org/10.1016/j.molcel.2019.09.009] [PMID: 31606272]
[11]
Li, Z.; Zhu, C.; Ding, Y.; Fei, Y.; Lu, B. ATTEC: A potential new approach to target proteinopathies. Autophagy, 2020, 16(1), 185-187.
[http://dx.doi.org/10.1080/15548627.2019.1688556] [PMID: 31690177]
[12]
Tomoshige, S.; Ishikawa, M. PROTACs and other chemical protein degradation technologies for the treatment of neurodegenerative disorders. Angew. Chem. Int. Ed., 2021, 60(7), 3346-3354.
[http://dx.doi.org/10.1002/anie.202004746] [PMID: 32410219]
[13]
Ma, A.; Stratikopoulos, E.; Park, K.S.; Wei, J.; Martin, T.C.; Yang, X.; Schwarz, M.; Leshchenko, V.; Rialdi, A.; Dale, B.; Lagana, A.; Guccione, E.; Parekh, S.; Parsons, R.; Jin, J. Discovery of a first-in-class EZH2 selective degrader. Nat. Chem. Biol., 2020, 16(2), 214-222.
[http://dx.doi.org/10.1038/s41589-019-0421-4] [PMID: 31819273]
[14]
Pike, A.C.; Brzozowski, A.M.; Walton, J.; Hubbard, R.E.; Thorsell, A.G.; Li, Y.L.; Gustafsson, J.A.; Carlquist, M. Structural insights into the mode of action of a pure antiestrogen. Structure, 2001, 9(2), 145-153.
[15]
Wijayaratne, A.L.; McDonnell, D.P. The human estrogen receptor-alpha is a ubiquitinated protein whose stability is affected differentially by agonists, antagonists, and selective estrogen receptor modulators. J. Biol. Chem., 2001, 276(38), 35684-35692.
[http://dx.doi.org/10.1074/jbc.M101097200] [PMID: 11473106]
[16]
Neklesa, T.K.; Tae, H.S.; Schneekloth, A.R.; Stulberg, M.J.; Corson, T.W.; Sundberg, T.B.; Raina, K.; Holley, S.A.; Crews, C.M. Small-molecule hydrophobic tagging–induced degradation of HaloTag fusion proteins. Nat. Chem. Biol., 2011, 7(8), 538-543.
[http://dx.doi.org/10.1038/nchembio.597] [PMID: 21725302]
[17]
Tae, H.S.; Sundberg, T.B.; Neklesa, T.K.; Noblin, D.J.; Gustafson, J.L.; Roth, A.G.; Raina, K.; Crews, C.M. Identification of hydrophobic tags for the degradation of stabilized proteins. ChemBioChem, 2012, 13(4), 538-541.
[http://dx.doi.org/10.1002/cbic.201100793] [PMID: 22271667]
[18]
Neklesa, T.K.; Noblin, D.J.; Kuzin, A.; Lew, S.; Seetharaman, J.; Acton, T.B.; Kornhaber, G.; Xiao, R.; Montelione, G.T.; Tong, L.; Crews, C.M. A bidirectional system for the dynamic small molecule control of intracellular fusion proteins. ACS Chem. Biol., 2013, 8(10), 2293-2300.
[http://dx.doi.org/10.1021/cb400569k] [PMID: 23978068]
[19]
Xie, T.; Lim, S.M.; Westover, K.D.; Dodge, M.E.; Ercan, D.; Ficarro, S.B.; Udayakumar, D.; Gurbani, D.; Tae, H.S.; Riddle, S.M.; Sim, T.; Marto, J.A.; Jänne, P.A.; Crews, C.M.; Gray, N.S. Pharmacological targeting of the pseudokinase Her3. Nat. Chem. Biol., 2014, 10(12), 1006-1012.
[http://dx.doi.org/10.1038/nchembio.1658] [PMID: 25326665]
[20]
Smith, M.H.; Ploegh, H.L.; Weissman, J.S. Road to ruin: Targeting proteins for degradation in the endoplasmic reticulum. Science, 2011, 334(6059), 1086-1090.
[http://dx.doi.org/10.1126/science.1209235] [PMID: 22116878]
[21]
Raina, K.; Noblin, D.J.; Serebrenik, Y.V.; Adams, A.; Zhao, C.; Crews, C.M. Targeted protein destabilization reveals an estrogen-mediated ER stress response. Nat. Chem. Biol., 2014, 10(11), 957-962.
[http://dx.doi.org/10.1038/nchembio.1638] [PMID: 25242550]
[22]
Gustafson, J.L.; Neklesa, T.K.; Cox, C.S.; Roth, A.G.; Buckley, D.L.; Tae, H.S.; Sundberg, T.B.; Stagg, D.B.; Hines, J.; McDonnell, D.P.; Norris, J.D.; Crews, C.M. Small-molecule-mediated degradation of the androgen receptor through hydrophobic tagging. Angew. Chem. Int. Ed., 2015, 54(33), 9659-9662.
[http://dx.doi.org/10.1002/anie.201503720] [PMID: 26083457]
[23]
Taylor, J.P.; Hardy, J.; Fischbeck, K.H. Toxic proteins in neurodegenerative disease. Science, 2002, 296(5575), 1991-1995.
[http://dx.doi.org/10.1126/science.1067122] [PMID: 12065827]
[24]
Hartl, F.U.; Bracher, A.; Hayer-Hartl, M. Molecular chaperones in protein folding and proteostasis. Nature, 2011, 475(7356), 324-332.
[http://dx.doi.org/10.1038/nature10317] [PMID: 21776078]
[25]
Kim, Y.E.; Hipp, M.S.; Bracher, A.; Hayer-Hartl, M.; Ulrich Hartl, F. Molecular chaperone functions in protein folding and proteostasis. Annu. Rev. Biochem., 2013, 82(1), 323-355.
[http://dx.doi.org/10.1146/annurev-biochem-060208-092442] [PMID: 23746257]
[26]
Kettern, N.; Dreiseidler, M.; Tawo, R.; Höhfeld, J. Chaperone-assisted degradation: Multiple paths to destruction. Biol. Chem., 2010, 391(5), 481-489.
[http://dx.doi.org/10.1515/bc.2010.058] [PMID: 20302520]
[27]
McDonough, H.; Patterson, C. CHIP: A link between the chaperone and proteasome systems. Cell Stress Chaperones, 2003, 8(4), 303-308.
[http://dx.doi.org/10.1379/1466-1268(2003)008<0303:CALBTC>2.0.CO;2] [PMID: 15115282]
[28]
Liu, Z.S.; Cai, H.; Xue, W.; Wang, M.; Xia, T.; Li, W.J.; Xing, J.Q.; Zhao, M.; Huang, Y.J.; Chen, S.; Wu, S.M.; Wang, X.; Liu, X.; Pang, X.; Zhang, Z.Y.; Li, T.; Dai, J.; Dong, F.; Xia, Q.; Li, A.L.; Zhou, T.; Liu, Z.; Zhang, X.M.; Li, T. G3BP1 promotes DNA binding and activation of cGAS. Nat. Immunol., 2019, 20(1), 18-28.
[http://dx.doi.org/10.1038/s41590-018-0262-4] [PMID: 30510222]
[29]
Yoshida, H. ER stress and diseases. FEBS J., 2007, 274(3), 630-658.
[http://dx.doi.org/10.1111/j.1742-4658.2007.05639.x] [PMID: 17288551]
[30]
Salter, J.D.; Smith, H.C. Modeling the embrace of a mutator: Apobec selection of nucleic acid ligands. Trends Biochem. Sci., 2018, 43(8), 606-622.
[http://dx.doi.org/10.1016/j.tibs.2018.04.013] [PMID: 29803538]
[31]
Sheng, Q.; Liu, X.; Fleming, E.; Yuan, K.; Piao, H.; Chen, J.; Moustafa, Z.; Thomas, R.K.; Greulich, H.; Schinzel, A.; Zaghlul, S.; Batt, D.; Ettenberg, S.; Meyerson, M.; Schoeberl, B.; Kung, A.L.; Hahn, W.C.; Drapkin, R.; Livingston, D.M.; Liu, J.F. An activated ErbB3/NRG1 autocrine loop supports in vivo proliferation in ovarian cancer cells. Cancer Cell, 2010, 17(3), 298-310.
[http://dx.doi.org/10.1016/j.ccr.2009.12.047] [PMID: 20227043]
[32]
Liu, Q.; Sabnis, Y.; Zhao, Z.; Zhang, T.; Buhrlage, S.J.; Jones, L.H.; Gray, N.S. Developing irreversible inhibitors of the protein kinase cysteinome. Chem. Biol., 2013, 20(2), 146-159.
[http://dx.doi.org/10.1016/j.chembiol.2012.12.006] [PMID: 23438744]
[33]
Strebhardt, K. Multifaceted polo-like kinases: Drug targets and antitargets for cancer therapy. Nat. Rev. Drug Discov., 2010, 9(8), 643-660.
[http://dx.doi.org/10.1038/nrd3184] [PMID: 20671765]
[34]
Elia, A.E.H.; Cantley, L.C.; Yaffe, M.B. Proteomic screen finds pSer/pThr-binding domain localizing Plk1 to mitotic substrates. Science, 2003, 299(5610), 1228-1231.
[http://dx.doi.org/10.1126/science.1079079] [PMID: 12595692]
[35]
Elia, A.E.H.; Rellos, P.; Haire, L.F.; Chao, J.W.; Ivins, F.J.; Hoepker, K.; Mohammad, D.; Cantley, L.C.; Smerdon, S.J.; Yaffe, M.B. The molecular basis for phosphodependent substrate targeting and regulation of Plks by the Polo-box domain. Cell, 2003, 115(1), 83-95.
[http://dx.doi.org/10.1016/S0092-8674(03)00725-6] [PMID: 14532005]
[36]
Scharow, A.; Raab, M.; Saxena, K.; Sreeramulu, S.; Kudlinzki, D.; Gande, S.; Dötsch, C.; Kurunci-Csacsko, E.; Klaeger, S.; Kuster, B.; Schwalbe, H.; Strebhardt, K.; Berg, T. Optimized Plk1 PBD inhibitors based on poloxin induce mitotic arrest and apoptosis in tumor cells. ACS Chem. Biol., 2015, 10(11), 2570-2579.
[http://dx.doi.org/10.1021/acschembio.5b00565] [PMID: 26279064]
[37]
Rubner, S.; Scharow, A.; Schubert, S.; Berg, T. Selective degradation of polo-like kinase 1 by a hydrophobically tagged inhibitor of the polo-box domain. Angew. Chem. Int. Ed., 2018, 57(52), 17043-17047.
[http://dx.doi.org/10.1002/anie.201809640] [PMID: 30351497]
[38]
Rubner, S.; Schubert, S.; Berg, T. Poloxin-2HT+: Changing the hydrophobic tag of Poloxin-2HT increases Plk1 degradation and apoptosis induction in tumor cells. Org. Biomol. Chem., 2019, 17(12), 3113-3117.
[http://dx.doi.org/10.1039/C9OB00080A] [PMID: 30848278]
[39]
Zhang, R.; Huang, C.; Xiao, X.; Zhou, J. Improving strategies in the development of protein-downregulation-based antiandrogens. ChemMedChem, 2021, 16(13), 2021-2033.
[http://dx.doi.org/10.1002/cmdc.202100033] [PMID: 33554455]
[40]
Balbas, M.D.; Evans, M.J.; Hosfield, D.J.; Wongvipat, J.; Arora, V.K.; Watson, P.A.; Chen, Y.; Greene, G.L.; Shen, Y.; Sawyers, C.L. Overcoming mutation-based resistance to antiandrogens with rational drug design. eLife, 2013, 2, e00499.
[http://dx.doi.org/10.7554/eLife.00499] [PMID: 23580326]
[41]
Xie, H.; Liang, J.J.; Wang, Y.L.; Hu, T.X.; Wang, J.Y.; Yang, R.H.; Yan, J.K.; Zhang, Q.R.; Xu, X.; Liu, H.M.; Ke, Y. The design, synthesis and anti-tumor mechanism study of new androgen receptor degrader. Eur. J. Med. Chem., 2020, 204, 112512.
[http://dx.doi.org/10.1016/j.ejmech.2020.112512] [PMID: 32736229]
[42]
Ballatore, C.; Lee, V.M.Y.; Trojanowski, J.Q. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat. Rev. Neurosci., 2007, 8(9), 663-672.
[http://dx.doi.org/10.1038/nrn2194] [PMID: 17684513]
[43]
Bouwman, F.H.; Schoonenboom, N.S.M.; Verwey, N.A.; van Elk, E.J.; Kok, A.; Blankenstein, M.A.; Scheltens, P.; van der Flier, W.M. CSF biomarker levels in early and late onset Alzheimer’s disease. Neurobiol. Aging, 2009, 30(12), 1895-1901.
[http://dx.doi.org/10.1016/j.neurobiolaging.2008.02.007] [PMID: 18403055]
[44]
Vossel, K.A.; Zhang, K.; Brodbeck, J.; Daub, A.C.; Sharma, P.; Finkbeiner, S.; Cui, B.; Mucke, L. Tau reduction prevents Abeta-induced defects in axonal transport. Science, 2010, 330(6001), 198.
[http://dx.doi.org/10.1126/science.1194653] [PMID: 20829454]
[45]
Roberson, E.D.; Scearce-Levie, K.; Palop, J.J.; Yan, F.; Cheng, I.H.; Wu, T.; Gerstein, H.; Yu, G.Q.; Mucke, L. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science, 2007, 316(5825), 750-754.
[http://dx.doi.org/10.1126/science.1141736] [PMID: 17478722]
[46]
Ittner, L.M.; Ke, Y.D.; Delerue, F.; Bi, M.; Gladbach, A.; van Eersel, J.; Wölfing, H.; Chieng, B.C.; Christie, M.J.; Napier, I.A.; Eckert, A.; Staufenbiel, M.; Hardeman, E.; Götz, J. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell, 2010, 142(3), 387-397.
[http://dx.doi.org/10.1016/j.cell.2010.06.036] [PMID: 20655099]
[47]
Gao, N.; Chu, T.T.; Li, Q.Q.; Lim, Y.J.; Qiu, T.; Ma, M.R.; Hu, Z.W.; Yang, X.F.; Chen, Y.X.; Zhao, Y.F.; Li, Y.M. Hydrophobic tagging-mediated degradation of Alzheimer’s disease related Tau. RSC Advances, 2017, 7(64), 40362-40366.
[http://dx.doi.org/10.1039/C7RA05347A]
[48]
Wils, H.; Kleinberger, G.; Janssens, J.; Pereson, S.; Joris, G.; Cuijt, I.; Smits, V.; Ceuterick-de Groote, C.; Van Broeckhoven, C.; Kumar-Singh, S. TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc. Natl. Acad. Sci. USA, 2010, 107(8), 3858-3863.
[http://dx.doi.org/10.1073/pnas.0912417107] [PMID: 20133711]
[49]
Gao, N.; Huang, Y.P.; Chu, T.T.; Li, Q.Q.; Zhou, B.; Chen, Y.X.; Zhao, Y.F.; Li, Y.M. TDP-43 specific reduction induced by Di-hydrophobic tags conjugated peptides. Bioorg. Chem., 2019, 84, 254-259.
[http://dx.doi.org/10.1016/j.bioorg.2018.11.042] [PMID: 30508770]
[50]
Hamroun, D.; Kato, S.; Ishioka, C.; Claustres, M.; Béroud, C.; Soussi, T. The UMD TP53 database and website: Update and revisions. Hum. Mutat., 2006, 27(1), 14-20.
[http://dx.doi.org/10.1002/humu.20269] [PMID: 16278824]
[51]
Freedman, D.A.; Wu, L.; Levine, A.J. Functions of the MDM2 oncoprotein. Cell. Mol. Life Sci., 1999, 55(1), 96-107.
[http://dx.doi.org/10.1007/s000180050273] [PMID: 10065155]
[52]
Estrada-Ortiz, N.; Neochoritis, C.G.; Dömling, A. How to design a successful p53-MDM2/X interaction inhibitor: A thorough overview based on crystal structures. ChemMedChem, 2016, 11(8), 757-772.
[http://dx.doi.org/10.1002/cmdc.201500487] [PMID: 26676832]
[53]
Nietzold, F.; Rubner, S.; Berg, T. The hydrophobically-tagged MDM2–p53 interaction inhibitor Nutlin-3a-HT is more potent against tumor cells than Nutlin-3a. Chem. Commun. (Camb.), 2019, 55(95), 14351-14354.
[http://dx.doi.org/10.1039/C9CC07795B] [PMID: 31720601]
[54]
Weaver, A.N.; Yang, E.S. Beyond DNA repair: Additional functions of PARP-1 in cancer. Front. Oncol., 2013, 3, 290.
[http://dx.doi.org/10.3389/fonc.2013.00290] [PMID: 24350055]
[55]
Narod, S.A.; Foulkes, W.D. BRCA1 and BRCA2: 1994 and beyond. Nat. Rev. Cancer, 2004, 4(9), 665-676.
[http://dx.doi.org/10.1038/nrc1431] [PMID: 15343273]
[56]
Go, A.; Jang, J.W.; Lee, W.; Ha, J.D.; Kim, H.J.; Nam, H.J. Augmentation of the antitumor effects of PARP inhibitors in triple-negative breast cancer via degradation by hydrophobic tagging modulation. Eur. J. Med. Chem., 2020, 204, 112635.
[http://dx.doi.org/10.1016/j.ejmech.2020.112635] [PMID: 32726747]
[57]
Oñate, S.A.; Tsai, S.Y.; Tsai, M.J.; O’Malley, B.W. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science, 1995, 270(5240), 1354-1357.
[http://dx.doi.org/10.1126/science.270.5240.1354] [PMID: 7481822]
[58]
Xu, J.; Wu, R.C.; O’Malley, B.W. Normal and cancer-related functions of the p160 steroid receptor co-activator (SRC) family. Nat. Rev. Cancer, 2009, 9(9), 615-630.
[http://dx.doi.org/10.1038/nrc2695] [PMID: 19701241]
[59]
Nikolovska-Coleska, Z.; Wang, R.; Fang, X.; Pan, H.; Tomita, Y.; Li, P.; Roller, P.P.; Krajewski, K.; Saito, N.G.; Stuckey, J.A.; Wang, S. Development and optimization of a binding assay for the XIAP BIR3 domain using fluorescence polarization. Anal. Biochem., 2004, 332(2), 261-273.
[http://dx.doi.org/10.1016/j.ab.2004.05.055] [PMID: 15325294]
[60]
Lee, Y.; Yoon, H.; Hwang, S.M.; Shin, M.K.; Lee, J.H.; Oh, M.; Im, S.H.; Song, J.; Lim, H.S. Targeted inhibition of the NCOA1/STAT6 protein–protein interaction. J. Am. Chem. Soc., 2017, 139(45), 16056-16059.
[http://dx.doi.org/10.1021/jacs.7b08972] [PMID: 29090910]
[61]
Choi, S.R.; Wang, H.M.; Shin, M.H.; Lim, H.S. Hydrophobic tagging-mediated degradation of transcription coactivator SRC-1. Int. J. Mol. Sci., 2021, 22(12), 6407.
[http://dx.doi.org/10.3390/ijms22126407] [PMID: 34203850]
[62]
Cao, R.; Wang, L.; Wang, H.; Xia, L.; Erdjument-Bromage, H.; Tempst, P.; Jones, R.S.; Zhang, Y. Role of histone H3 lysine 27 methylation in polycomb-group silencing. Science, 2002, 298(5595), 1039-1043.
[http://dx.doi.org/10.1126/science.1076997] [PMID: 12351676]
[63]
Kuzmichev, A.; Nishioka, K.; Erdjument-Bromage, H.; Tempst, P.; Reinberg, D. Histone methyltransferase activity associated with a human multiprotein complex containing the enhancer of zeste protein. Genes Dev., 2002, 16(22), 2893-2905.
[http://dx.doi.org/10.1101/gad.1035902] [PMID: 12435631]
[64]
Kim, K.H.; Roberts, C.W.M. Targeting EZH2 in cancer. Nat. Med., 2016, 22(2), 128-134.
[http://dx.doi.org/10.1038/nm.4036] [PMID: 26845405]
[65]
Kaniskan, H.Ü.; Martini, M.L.; Jin, J. Inhibitors of protein methyltransferases and demethylases. Chem. Rev., 2018, 118(3), 989-1068.
[http://dx.doi.org/10.1021/acs.chemrev.6b00801] [PMID: 28338320]
[66]
Waters, A.M.; Der, C.J. KRAS: The critical driver and therapeutic target for pancreatic cancer. Cold Spring Harb. Perspect. Med., 2018, 8(9), a031435.
[http://dx.doi.org/10.1101/cshperspect.a031435] [PMID: 29229669]
[67]
Cox, A.D.; Fesik, S.W.; Kimmelman, A.C.; Luo, J.; Der, C.J. Drugging the undruggable RAS: Mission possible? Nat. Rev. Drug Discov., 2014, 13(11), 828-851.
[http://dx.doi.org/10.1038/nrd4389] [PMID: 25323927]
[68]
Kessler, D.; Gmachl, M.; Mantoulidis, A.; Martin, L.J.; Zoephel, A.; Mayer, M.; Gollner, A.; Covini, D.; Fischer, S.; Gerstberger, T.; Gmaschitz, T.; Goodwin, C.; Greb, P.; Häring, D.; Hela, W.; Hoffmann, J.; Karolyi-Oezguer, J.; Knesl, P.; Kornigg, S.; Koegl, M.; Kousek, R.; Lamarre, L.; Moser, F.; Munico-Martinez, S.; Peinsipp, C.; Phan, J.; Rinnenthal, J.; Sai, J.; Salamon, C.; Scherbantin, Y.; Schipany, K.; Schnitzer, R.; Schrenk, A.; Sharps, B.; Siszler, G.; Sun, Q.; Waterson, A.; Wolkerstorfer, B.; Zeeb, M.; Pearson, M.; Fesik, S.W.; McConnell, D.B. Drugging an undruggable pocket on KRAS. Proc. Natl. Acad. Sci. USA, 2019, 116(32), 15823-15829.
[http://dx.doi.org/10.1073/pnas.1904529116] [PMID: 31332011]
[69]
Chen, F.; Alphonse, M.P.; Liu, Y.; Liu, Q. Targeting mutant KRAS for anticancer therapy. Curr. Top. Med. Chem., 2019, 19(23), 2098-2113.
[http://dx.doi.org/10.2174/1568026619666190902151307] [PMID: 31475898]
[70]
Liu, P.; Wang, Y.; Li, X. Targeting the untargetable KRAS in cancer therapy. Acta Pharm. Sin. B, 2019, 9(5), 871-879.
[http://dx.doi.org/10.1016/j.apsb.2019.03.002] [PMID: 31649840]
[71]
Klein, C.H.; Truxius, D.C.; Vogel, H.A.; Harizanova, J.; Murarka, S.; Martín-Gago, P.; Bastiaens, P.I.H. PDEδ inhibition impedes the proliferation and survival of human colorectal cancer cell lines harboring oncogenic KRas. Int. J. Cancer, 2019, 144(4), 767-776.
[http://dx.doi.org/10.1002/ijc.31859] [PMID: 30194764]
[72]
Guo, M.; He, S.; Cheng, J.; Li, Y.; Dong, G.; Sheng, C. Hydrophobic tagging-induced degradation of PDEδ in colon cancer cells. ACS Med. Chem. Lett., 2022, 13(2), 298-303.
[http://dx.doi.org/10.1021/acsmedchemlett.1c00670] [PMID: 35178186]
[73]
Hu, J.; Hu, B.; Wang, M.; Xu, F.; Miao, B.; Yang, C.Y.; Wang, M.; Liu, Z.; Hayes, D.F.; Chinnaswamy, K.; Delproposto, J.; Stuckey, J.; Wang, S. Discovery of ERD-308 as a highly potent proteolysis targeting chimera (PROTAC) degrader of estrogen receptor (ER). J. Med. Chem., 2019, 62(3), 1420-1442.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01572] [PMID: 30990042]
[74]
Harvey, J.M.; Clark, G.M.; Osborne, C.K.; Allred, D.C. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J. Clin. Oncol., 1999, 17(5), 1474-1481.
[http://dx.doi.org/10.1200/JCO.1999.17.5.1474] [PMID: 10334533]
[75]
Liang, J.; Zbieg, J.R.; Blake, R.A.; Chang, J.H.; Daly, S.; DiPasquale, A.G.; Friedman, L.S.; Gelzleichter, T.; Gill, M.; Giltnane, J.M.; Goodacre, S.; Guan, J.; Hartman, S.J.; Ingalla, E.R.; Kategaya, L.; Kiefer, J.R.; Kleinheinz, T.; Labadie, S.S.; Lai, T.; Li, J.; Liao, J.; Liu, Z.; Mody, V.; McLean, N.; Metcalfe, C.; Nannini, M.A.; Oeh, J.; O’Rourke, M.G.; Ortwine, D.F.; Ran, Y.; Ray, N.C.; Roussel, F.; Sambrone, A.; Sampath, D.; Schutt, L.K.; Vinogradova, M.; Wai, J.; Wang, T.; Wertz, I.E.; White, J.R.; Yeap, S.K.; Young, A.; Zhang, B.; Zheng, X.; Zhou, W.; Zhong, Y.; Wang, X. GDC-9545 (Giredestrant): A potent and orally bioavailable selective estrogen receptor antagonist and degrader with an exceptional preclinical profile for er+ breast cancer. J. Med. Chem., 2021, 64(16), 11841-11856.
[http://dx.doi.org/10.1021/acs.jmedchem.1c00847] [PMID: 34251202]
[76]
Dheer, D.; Behera, C.; Singh, D.; Abdullaha, M.; Chashoo, G.; Bharate, S.B.; Gupta, P.N.; Shankar, R. Design, synthesis and comparative analysis of triphenyl-1,2,3-triazoles as anti-proliferative agents. Eur. J. Med. Chem., 2020, 207, 112813.
[http://dx.doi.org/10.1016/j.ejmech.2020.112813] [PMID: 32947093]
[77]
Scott, J.S.; Bailey, A.; Davies, R.D.M.; Degorce, S.L.; MacFaul, P.A.; Gingell, H.; Moss, T.; Norman, R.A.; Pink, J.H.; Rabow, A.A.; Roberts, B.; Smith, P.D. Tetrahydroisoquinoline phenols: Selective estrogen receptor downregulator antagonists with oral bioavailability in rat. ACS Med. Chem. Lett., 2016, 7(1), 94-99.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00413] [PMID: 26819673]
[78]
Abdel-Magid, A.F. Selective estrogen receptor degraders (SERDs): A promising treatment to overcome resistance to endocrine therapy in ERα-positive breast cancer. ACS Med. Chem. Lett., 2017, 8(11), 1129-1131.
[http://dx.doi.org/10.1021/acsmedchemlett.7b00424] [PMID: 29152041]
[79]
Zhao, Y.; Zhao, C.; Lu, J.; Wu, J.; Li, C.; Hu, Z.; Tian, W.; Yang, L.; Xiang, J.; Zhou, H.; Deng, Z.; Huang, J.; Hong, K. Sesterterpene MHO7 suppresses breast cancer cells as a novel estrogen receptor degrader. Pharmacol. Res., 2019, 146, 104294.
[http://dx.doi.org/10.1016/j.phrs.2019.104294] [PMID: 31175940]
[80]
He, S.; Dong, G.; Cheng, J.; Wu, Y.; Sheng, C. Strategies for designing proteolysis targeting chimaeras (PROTACs). Med. Res. Rev., 2022, 42(3), 1280-1342.
[http://dx.doi.org/10.1002/med.21877] [PMID: 35001407]
[81]
Paiva, S.L.; Crews, C.M. Targeted protein degradation: Elements of PROTAC design. Curr. Opin. Chem. Biol., 2019, 50, 111-119.
[http://dx.doi.org/10.1016/j.cbpa.2019.02.022] [PMID: 31004963]
[82]
Endo, Y.; Iijima, T.; Kagechika, H.; Ohta, K.; Kawachi, E.; Shudo, K. Dicarba-closo-dodecaboranes as a pharmacophore. Novel potent retinoidal agonists. Chem. Pharm. Bull. (Tokyo), 1999, 47(4), 585-587.
[http://dx.doi.org/10.1248/cpb.47.585] [PMID: 10319433]
[83]
Julius, R.L.; Farha, O.K.; Chiang, J.; Perry, L.J.; Hawthorne, M.F. Synthesis and evaluation of transthyretin amyloidosis inhibitors containing carborane pharmacophores. Proc. Natl. Acad. Sci. USA, 2007, 104(12), 4808-4813.
[http://dx.doi.org/10.1073/pnas.0700316104] [PMID: 17360344]
[84]
Asawa, Y.; Nishida, K.; Kawai, K.; Domae, K.; Ban, H.S.; Kitazaki, A.; Asami, H.; Kohno, J.Y.; Okada, S.; Tokuma, H.; Sakano, D.; Kume, S.; Tanaka, M.; Nakamura, H. Carborane as an alternative efficient hydrophobic tag for protein degradation. Bioconjug. Chem., 2021, 32(11), 2377-2385.
[http://dx.doi.org/10.1021/acs.bioconjchem.1c00431] [PMID: 34699716]
[85]
Burslem, G.M.; Smith, B.E.; Lai, A.C.; Jaime-Figueroa, S.; McQuaid, D.C.; Bondeson, D.P.; Toure, M.; Dong, H.; Qian, Y.; Wang, J.; Crew, A.P.; Hines, J.; Crews, C.M. The advantages of targeted protein degradation over inhibition: An RTK case study. Cell Chem. Biol., 2018, 25(1), 67-77.e3.
[http://dx.doi.org/10.1016/j.chembiol.2017.09.009] [PMID: 29129716]
[86]
Zoppi, V.; Hughes, S.J.; Maniaci, C.; Testa, A.; Gmaschitz, T.; Wieshofer, C.; Koegl, M.; Riching, K.M.; Daniels, D.L.; Spallarossa, A.; Ciulli, A. Iterative design and optimization of initially inactive proteolysis targeting chimeras (PROTACs) Identify VZ185 as a potent, fast, and selective von Hippel–Lindau (VHL) based dual degrader probe of BRD9 and BRD7. J. Med. Chem., 2019, 62(2), 699-726.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01413] [PMID: 30540463]
[87]
Han, X.; Wang, C.; Qin, C.; Xiang, W.; Fernandez-Salas, E.; Yang, C.Y.; Wang, M.; Zhao, L.; Xu, T.; Chinnaswamy, K.; Delproposto, J.; Stuckey, J.; Wang, S. Discovery of ARD-69 as a highly potent proteolysis targeting chimera (PROTAC) degrader of androgen receptor (AR) for the treatment of prostate cancer. J. Med. Chem., 2019, 62(2), 941-964.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01631] [PMID: 30629437]
[88]
Bemis, T.A.; La Clair, J.J.; Burkart, M.D. Unraveling the role of linker design in proteolysis targeting chimeras. J. Med. Chem., 2021, 64(12), 8042-8052.
[http://dx.doi.org/10.1021/acs.jmedchem.1c00482] [PMID: 34106704]
[89]
Li, X.; Lü, Z.; Wang, C.; Li, K.; Xu, F.; Xu, P.; Niu, Y. Induction of apoptosis in cancer cells by glutathione transferase inhibitor mediated hydrophobic tagging molecules. ACS Med. Chem. Lett., 2021, 12(5), 720-725.
[http://dx.doi.org/10.1021/acsmedchemlett.0c00627] [PMID: 34055217]
[90]
Itoh, Y.; Ishikawa, M.; Naito, M.; Hashimoto, Y. Protein knockdown using methyl bestatin-ligand hybrid molecules: Design and synthesis of inducers of ubiquitination-mediated degradation of cellular retinoic acid-binding proteins. J. Am. Chem. Soc., 2010, 132(16), 5820-5826.
[http://dx.doi.org/10.1021/ja100691p] [PMID: 20369832]
[91]
Lai, A.C.; Toure, M.; Hellerschmied, D.; Salami, J.; Jaime-Figueroa, S.; Ko, E.; Hines, J.; Crews, C.M. Modular PROTAC design for the degradation of oncogenic BCR-ABL. Angew. Chem. Int. Ed., 2016, 55(2), 807-810.
[http://dx.doi.org/10.1002/anie.201507634] [PMID: 26593377]
[92]
Farnaby, W.; Koegl, M.; Roy, M.J.; Whitworth, C.; Diers, E.; Trainor, N.; Zollman, D.; Steurer, S.; Karolyi-Oezguer, J.; Riedmueller, C.; Gmaschitz, T.; Wachter, J.; Dank, C.; Galant, M.; Sharps, B.; Rumpel, K.; Traxler, E.; Gerstberger, T.; Schnitzer, R.; Petermann, O.; Greb, P.; Weinstabl, H.; Bader, G.; Zoephel, A.; Weiss-Puxbaum, A.; Ehrenhöfer-Wölfer, K.; Wöhrle, S.; Boehmelt, G.; Rinnenthal, J.; Arnhof, H.; Wiechens, N.; Wu, M.Y.; Owen-Hughes, T.; Ettmayer, P.; Pearson, M.; McConnell, D.B.; Ciulli, A. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat. Chem. Biol., 2019, 15(7), 672-680.
[http://dx.doi.org/10.1038/s41589-019-0294-6] [PMID: 31178587]
[93]
Xiang, W.; Zhao, L.; Han, X.; Qin, C.; Miao, B.; McEachern, D.; Wang, Y.; Metwally, H.; Kirchhoff, P.D.; Wang, L.; Matvekas, A.; He, M.; Wen, B.; Sun, D.; Wang, S. Discovery of ARD-2585 as an exceptionally potent and orally active PROTAC degrader of androgen receptor for the treatment of advanced prostate cancer. J. Med. Chem., 2021, 64(18), 13487-13509.
[http://dx.doi.org/10.1021/acs.jmedchem.1c00900] [PMID: 34473519]

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