Targeted Protein Degradation and Regulation with Molecular Glue:
Past and Recent Discoveries

Yizheng       Fang; Qiaojun       He; Ji       Cao
Abstract

The evolution in research and clinical settings of targeted therapies has been inspired by the progress of cancer chemotherapy to use small molecules and monoclonal antibodies for targeting specific disease-associated genes and proteins for noninfectious chronic diseases. In addition to conventional protein inhibition and activation strategies as drug discovery modalities, new methods of targeted protein degradation and regulation using molecular glues have become an attractive approach for drug discovery. Mechanistically, molecular glues trigger interactions between the proteins that originally did not interact by forming ternary complexes as protein-protein interaction (PPI) modulators. New molecular glues and their mechanisms of action have been actively investigated in the past decades. An immunomodulatory imide drug, thalidomide, and its derivatives have been used in the clinic and are a class of molecular glue that induces degradation of several neo-substrates. In this review, we summarize the development of molecular glues and share our opinions on the identification of novel molecular glues in an attempt to promote the concept and inspire further investigations.
Keywords: Molecular glue, protein degradation, protein-protein interaction, thalidomide, CR8, E7820.
[1] 
Toure, M.; Crews, C.M. Small-molecule protacs: new approaches to protein degradation. Angew. Chem. Int. Ed. Engl.,  2016, 55(6), 1966-1973.
[http://dx.doi.org/10.1002/anie.201507978] [PMID:  26756721] 
[2] 
Stanton, B.Z.; Chory, E.J.; Crabtree, G.R. Chemically induced proximity in biology and medicine. Science,  2018, 359(6380)eaao5902
[http://dx.doi.org/10.1126/science.aao5902] [PMID:  29590011] 
[3] 
Hughes, S.J.; Ciulli, A. Molecular recognition of ternary complexes: a new dimension in the structure-guided design of chemical degraders. Essays Biochem.,  2017, 61(5), 505-516.
[http://dx.doi.org/10.1042/EBC20170041] [PMID:  29118097] 
[4] 
Chopra, R.; Sadok, A.; Collins, I. A critical evaluation of the approaches to targeted protein degradation for drug discovery. Drug Discov. Today. Technol.,  2019, 31, 5-13.
[http://dx.doi.org/10.1016/j.ddtec.2019.02.002] [PMID:  31200859] 
[5] 
Du, X.; Volkov, O.A.; Czerwinski, R.M.; Tan, H.; Huerta, C.; Morton, E.R.; Rizzi, J.P.; Wehn, P.M.; Xu, R.; Nijhawan, D.; Wallace, E.M. Structural basis and kinetic pathway of RBM39 recruitment to DCAF15 by a sulfonamide molecular glue E7820.Structure, 2019, 27(11), 1625-1633
	e1623., 
[http://dx.doi.org/10.1016/j.str.2019.10.005] 
[6] 
Słabicki, M.; Kozicka, Z.; Petzold, G.; Li, Y-D.; Manojkumar, M.; Bunker, R.D.; Donovan, K.A.; Sievers, Q.L.; Koeppel, J.; Suchyta, D.; Sperling, A.S.; Fink, E.C.; Gasser, J.A.; Wang, L.R.; Corsello, S.M.; Sellar, R.S.; Jan, M.; Gillingham, D.; Scholl, C.; Fröhling, S.; Golub, T.R.; Fischer, E.S.; Thomä, N.H.; Ebert, B.L. The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K. Nature,  2020, 585(7824), 293-297.
[http://dx.doi.org/10.1038/s41586-020-2374-x] [PMID:  32494016] 
[7] 
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] 
[8] 
Bosch, J. PPI inhibitor and stabilizer development in human diseases. Drug Discov. Today. Technol.,  2017, 24, 3-9.
[http://dx.doi.org/10.1016/j.ddtec.2017.10.004] [PMID:  29233297] 
[9] 
Okuro, K.; Kinbara, K.; Tsumoto, K.; Ishii, N.; Aida, T. Molecular glues carrying multiple guanidinium ion pendants via an oligoether spacer: stabilization of microtubules against depolymerization. J. Am. Chem. Soc.,  2009, 131(5), 1626-1627.
[http://dx.doi.org/10.1021/ja800491v] [PMID:  19146374] 
[10] 
Schmidtchen, F.P.; Berger, M. Artificial organic host molecules for anions. Chem. Rev.,  1997, 97(5), 1609-1646.
[http://dx.doi.org/10.1021/cr9603845] [PMID:  11851460] 
[11] 
Lagoutte, R.; Winssinger, N. Following the lead from nature with covalent inhibitors. Chimia (Aarau),  2017, 71(10), 703-711.
[http://dx.doi.org/10.2533/chimia.2017.703] [PMID:  29070414] 
[12] 
Isobe, Y.; Okumura, M.; McGregor, L.M.; Brittain, S.M.; Jones, M.D.; Liang, X.; White, R.; Forrester, W.; McKenna, J.M.; Tallarico, J.A.; Schirle, M.; Maimone, T.J.; Nomura, D.K. Manumycin polyketides act as molecular glues between UBR7 and P53. Nat. Chem. Biol.,  2020, 16(11), 1189-1198.
[http://dx.doi.org/10.1038/s41589-020-0557-2] [PMID:  32572277] 
[13] 
Sheskin, J. Thalidomide in the treatment of lepra reactions. Clin. Pharmacol. Ther.,  1965, 6, 303-306.
[http://dx.doi.org/10.1002/cpt196563303] [PMID:  14296027] 
[14] 
Singhal, S.; Mehta, J.; Desikan, R.; Ayers, D.; Roberson, P.; Eddlemon, P.; Munshi, N.; Anaissie, E.; Wilson, C.; Dhodapkar, M.; Zeddis, J.; Barlogie, B. Antitumor activity of thalidomide in refractory multiple myeloma. N. Engl. J. Med.,  1999, 341(21), 1565-1571.
[http://dx.doi.org/10.1056/NEJM199911183412102] [PMID:  10564685] 
[15] 
Bramuzzo, M.; Ventura, A.; Martelossi, S.; Lazzerini, M. Thalidomide for inflammatory bowel disease: Systematic review. Medicine (Baltimore),  2016, 95(30)e4239
[http://dx.doi.org/10.1097/MD.0000000000004239] [PMID:  27472695] 
[16] 
Srinivasan, R.; Akobeng, A.K. Thalidomide and thalidomide analogues for induction of remission in Crohn’s disease. Cochrane Database Syst. Rev., 2009, (2)CD007350
[http://dx.doi.org/10.1002/14651858.CD007350.pub2] [PMID:  19370684] 
[17] 
Akobeng, A.K.; Stokkers, P.C. Thalidomide and thalidomide analogues for maintenance of remission in Crohn’s disease. Cochrane Database Syst. Rev., 2009, (2)CD007351
[http://dx.doi.org/10.1002/14651858.CD007351.pub2] [PMID:  19370685] 
[18] 
Fisher, S.L.; Phillips, A.J. Targeted protein degradation and the enzymology of degraders. Curr. Opin. Chem. Biol.,  2018, 44, 47-55.
[http://dx.doi.org/10.1016/j.cbpa.2018.05.004] [PMID:  29885948] 
[19] 
Gerry, C.J.; Schreiber, S.L. Unifying principles of bifunctional, proximity-inducing small molecules. Nat. Chem. Biol.,  2020, 16(4), 369-378.
[http://dx.doi.org/10.1038/s41589-020-0469-1] [PMID:  32198490] 
[20] 
Schreiber, S.L. The rise of molecular glues. Cell,  2021, 184(1), 3-9.
[http://dx.doi.org/10.1016/j.cell.2020.12.020] [PMID:  33417864] 
[21] 
Simonetta, K.R.; Taygerly, J.; Boyle, K.; Basham, S.E.; Padovani, C.; Lou, Y.; Cummins, T.J.; Yung, S.L.; von Soly, S.K.; Kayser, F.; Kuriyan, J.; Rape, M.; Cardozo, M.; Gallop, M.A.; Bence, N.F.; Barsanti, P.A.; Saha, A. Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction. Nat. Commun.,  2019, 10(1), 1402.
[http://dx.doi.org/10.1038/s41467-019-09358-9] [PMID:  30926793] 
[22] 
Knobloch, J.; Rüther, U. Shedding light on an old mystery: thalidomide suppresses survival pathways to induce limb defects. Cell Cycle,  2008, 7(9), 1121-1127.
[http://dx.doi.org/10.4161/cc.7.9.5793] [PMID:  18418038] 
[23] 
Ito, T.; Ando, H.; Suzuki, T.; Ogura, T.; Hotta, K.; Imamura, Y.; Yamaguchi, Y.; Handa, H. Identification of a primary target of thalidomide teratogenicity. Science,  2010, 327(5971), 1345-1350.
[http://dx.doi.org/10.1126/science.1177319] [PMID:  20223979] 
[24] 
Eichner, R.; Heider, M.; Fernández-Sáiz, V.; van Bebber, F.; Garz, A.K.; Lemeer, S.; Rudelius, M.; Targosz, B.S.; Jacobs, L.; Knorn, A.M.; Slawska, J.; Platzbecker, U.; Germing, U.; Langer, C.; Knop, S.; Einsele, H.; Peschel, C.; Haass, C.; Keller, U.; Schmid, B.; Götze, K.S.; Kuster, B.; Bassermann, F. Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity. Nat. Med.,  2016, 22(7), 735-743.
[http://dx.doi.org/10.1038/nm.4128] [PMID:  27294876] 
[25] 
Ito, T.; Handa, H. Molecular mechanisms of thalidomide and its derivatives. Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci.,  2020, 96(6), 189-203.
[http://dx.doi.org/10.2183/pjab.96.016] [PMID:  32522938] 
[26] 
Mori, T.; Ito, T.; Liu, S.; Ando, H.; Sakamoto, S.; Yamaguchi, Y.; Tokunaga, E.; Shibata, N.; Handa, H.; Hakoshima, T. Structural basis of thalidomide enantiomer binding to cereblon. Sci. Rep.,  2018, 8(1), 1294.
[http://dx.doi.org/10.1038/s41598-018-19202-7] [PMID:  29358579] 
[27] 
Fischer, E.S.; Böhm, K.; Lydeard, J.R.; Yang, H.; Stadler, M.B.; Cavadini, S.; Nagel, J.; Serluca, F.; Acker, V.; Lingaraju, G.M.; Tichkule, R.B.; Schebesta, M.; Forrester, W.C.; Schirle, M.; Hassiepen, U.; Ottl, J.; Hild, M.; Beckwith, R.E.; Harper, J.W.; Jenkins, J.L.; Thomä, N.H. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature,  2014, 512(7512), 49-53.
[http://dx.doi.org/10.1038/nature13527] [PMID:  25043012] 
[28] 
Kim, H.K.; Ko, T.H.; Nyamaa, B.; Lee, S.R.; Kim, N.; Ko, K.S.; Rhee, B.D.; Park, C.S.; Nilius, B.; Han, J. Cereblon in health and disease. Pflugers Arch.,  2016, 468(8), 1299-1309.
[http://dx.doi.org/10.1007/s00424-016-1854-1] [PMID:  27343012] 
[29] 
Ito, T.; Handa, H. Cereblon and its downstream substrates as molecular targets of immunomodulatory drugs. Int. J. Hematol.,  2016, 104(3), 293-299.
[http://dx.doi.org/10.1007/s12185-016-2073-4] [PMID:  27460676] 
[30] 
Vargesson, N. Thalidomide-induced teratogenesis: history and mechanisms. Birth Defects Res. C Embryo Today,  2015, 105(2), 140-156.
[http://dx.doi.org/10.1002/bdrc.21096] [PMID:  26043938] 
[31] 
Fischer, E.S.; Park, E.; Eck, M.J.; Thomä, N.H. SPLINTS: small-molecule protein ligand interface stabilizers. Curr. Opin. Struct. Biol.,  2016, 37, 115-122.
[http://dx.doi.org/10.1016/j.sbi.2016.01.004] [PMID:  26829757] 
[32] 
Li, Y.; Yang, J.; Aguilar, A.; McEachern, D.; Przybranowski, S.; Liu, L.; Yang, C.Y.; Wang, M.; Han, X.; Wang, S. Discovery of MD-224 as a first-in-class, highly potent, and efficacious proteolysis targeting chimera murine double minute 2 degrader capable of achieving complete and durable tumor regression. J. Med. Chem.,  2019, 62(2), 448-466.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00909] [PMID:  30525597] 
[33] 
Yi, K.; Xu, J.; Peng, B. The association between GSTP1 polymorphism and pre-eclampsia risk: a system review and meta-analysis. Arch. Gynecol. Obstet.,  2020, 301(1), 11-18.
[http://dx.doi.org/10.1007/s00404-019-05411-6] [PMID:  31875251] 
[34] 
Tao, N.N.; Zhou, H.Z.; Tang, H.; Cai, X.F.; Zhang, W.L.; Ren, J.H.; Zhou, L.; Chen, X.; Chen, K.; Li, W.Y.; Liu, B.; Yang, Q.X.; Cheng, S.T.; Huang, L.X.; Huang, A.L.; Chen, J. Sirtuin 3 enhanced drug sensitivity of human hepatoma cells through glutathione S-transferase pi 1/JNK signaling pathway. Oncotarget,  2016, 7(31), 50117-50130.
[http://dx.doi.org/10.18632/oncotarget.10319] [PMID:  27367026] 
[35] 
Yang, M.; Li, Y.; Shen, X.; Ruan, Y.; Lu, Y.; Jin, X.; Song, P.; Guo, Y.; Zhang, X.; Qu, H.; Shao, Y.; Quan, C. CLDN6 promotes chemoresistance through GSTP1 in human breast cancer. J. Exp. Clin. Cancer Res.,  2017, 36(1), 157.
[http://dx.doi.org/10.1186/s13046-017-0627-9] [PMID:  29116019] 
[36] 
Yang, J.; Li, Y.; Aguilar, A.; Liu, Z.; Yang, C.Y.; Wang, S. Simple structural modifications converting a bona fide MDM2 PROTAC degrader into a molecular glue molecule: a cautionary tale in the design of PROTAC degraders. J. Med. Chem.,  2019, 62(21), 9471-9487.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00846] [PMID:  31560543] 
[37] 
Bettayeb, K.; Oumata, N.; Echalier, A.; Ferandin, Y.; Endicott, J.A.; Galons, H.; Meijer, L. CR8, a potent and selective, roscovitine-derived inhibitor of cyclin-dependent kinases. Oncogene,  2008, 27(44), 5797-5807.
[http://dx.doi.org/10.1038/onc.2008.191] [PMID:  18574471] 
[38] 
Petzold, G.; Fischer, E.S.; Thomä, N.H. Structural basis of lenalidomide-induced CK1α degradation by the CRL4(CRBN) ubiquitin ligase. Nature,  2016, 532(7597), 127-130.
[http://dx.doi.org/10.1038/nature16979] [PMID:  26909574] 
[39] 
Lui, G.Y.L.; Grandori, C.; Kemp, C.J. CDK12: an emerging therapeutic target for cancer. J. Clin. Pathol.,  2018, 71(11), 957-962.
[http://dx.doi.org/10.1136/jclinpath-2018-205356] [PMID:  30104286] 
[40] 
Delehouzé, C.; Godl, K.; Loaëc, N.; Bruyère, C.; Desban, N.; Oumata, N.; Galons, H.; Roumeliotis, T.I.; Giannopoulou, E.G.; Grenet, J.; Twitchell, D.; Lahti, J.; Mouchet, N.; Galibert, M.D.; Garbis, S.D.; Meijer, L. CDK/CK1 inhibitors roscovitine and CR8 downregulate amplified MYCN in neuroblastoma cells. Oncogene,  2014, 33(50), 5675-5687.
[http://dx.doi.org/10.1038/onc.2013.513] [PMID:  24317512] 
[41] 
Semba, T.; Funahashi, Y.; Ono, N.; Yamamoto, Y.; Sugi, N.H.; Asada, M.; Yoshimatsu, K.; Wakabayashi, T. An angiogenesis inhibitor E7820 shows broad-spectrum tumor growth inhibition in a xenograft model: possible value of integrin alpha2 on platelets as a biological marker. Clin. Cancer Res.,  2004, 10(4), 1430-1438.
[http://dx.doi.org/10.1158/1078-0432.CCR-0109-03] [PMID:  14977846] 
[42] 
Han, T.; Goralski, M.; Gaskill, N.; Capota, E.; Kim, J.; Ting, T.C.; Xie, Y.; Williams, N.S.; Nijhawan, D. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science,  2017, 356(6336)eaal3755
[http://dx.doi.org/10.1126/science.aal3755] [PMID:  28302793] 
[43] 
Uehara, T.; Minoshima, Y.; Sagane, K.; Sugi, N.H.; Mitsuhashi, K.O.; Yamamoto, N.; Kamiyama, H.; Takahashi, K.; Kotake, Y.; Uesugi, M.; Yokoi, A.; Inoue, A.; Yoshida, T.; Mabuchi, M.; Tanaka, A.; Owa, T. Selective degradation of splicing factor CAPERα by anticancer sulfonamides. Nat. Chem. Biol.,  2017, 13(6), 675-680.
[http://dx.doi.org/10.1038/nchembio.2363] [PMID:  28437394] 
[44] 
McGaughey, G.B.; Gagné, M.; Rappé, A.K. pi-Stacking interactions. Alive and well in proteins. J. Biol. Chem.,  1998, 273(25), 15458-15463.
[http://dx.doi.org/10.1074/jbc.273.25.15458] [PMID:  9624131] 
[45] 
Baek, K.; Schulman, B.A. Molecular glue concept solidifies. Nat. Chem. Biol.,  2020, 16(1), 2-3.
[http://dx.doi.org/10.1038/s41589-019-0414-3] [PMID:  31819271] 
[46] 
Bury, M.; Andolfi, A.; Rogister, B.; Cimmino, A.; Mégalizzi, V.; Mathieu, V.; Feron, O.; Evidente, A.; Kiss, R. Fusicoccin a, a phytotoxic carbotricyclic diterpene glucoside of fungal origin, reduces proliferation and invasion of glioblastoma cells by targeting multiple tyrosine kinases. Transl. Oncol.,  2013, 6(2), 112-123.
[http://dx.doi.org/10.1593/tlo.12409] [PMID:  23544164] 
[47] 
Stevers, L.M.; Sijbesma, E.; Botta, M.; MacKintosh, C.; Obsil, T.; Landrieu, I.; Cau, Y.; Wilson, A.J.; Karawajczyk, A.; Eickhoff, J.; Davis, J.; Hann, M.; O’Mahony, G.; Doveston, R.G.; Brunsveld, L.; Ottmann, C. Modulators of 14-3-3 protein-protein interactions. J. Med. Chem.,  2018, 61(9), 3755-3778.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00574] [PMID:  28968506] 
[48] 
Layfield, R.; Fergusson, J.; Aitken, A.; Lowe, J.; Landon, M.; Mayer, R.J. Neurofibrillary tangles of Alzheimer’s disease brains contain 14-3-3 proteins. Neurosci. Lett.,  1996, 209(1), 57-60.
[http://dx.doi.org/10.1016/0304-3940(96)12598-2] [PMID:  8734909] 
[49] 
Ayuke, G.H. Baker, R. Beausejour, J. C. Bedano, K. Birkhofer, E. Blanchart, B. Blossey, T. Bolger, R. L. Bradley, M. A. Callaham, Y. Capowiez, M. E. Caulfield, A. Choi, F. V. Crotty, A. Davalos, D. J. Diaz Cosin, A. Dominguez, A. E. Duhour, N. van Eekeren, C. Emmerling, L. B. Falco, R. Fernandez, S. J. Fonte, C. Fragoso, A. L. C. Franco, M. Fugere, A. T. Fusilero, S. Gholami, M. J. Gundale, M. Gutierrez Lopez, D. K. Hackenberger, L. M. Hernandez, T. Hishi, A. R. Holdsworth, M. Holmstrup, K. N. Hopfensperger, E. Huerta Lwanga, V. Huhta, T. T. Hurisso, B. V. Iannone III, M. Iordache, M. Joschko, N. Kaneko, R. Kanianska, A. M. Keith, C. A. Kelly, M. L. Kernecker, J. Klaminder, A. W. Kone, Y. Kooch, S. T. Kukkonen, H. Lalthanzara, D. R. Lammel, I. M. Lebedev, Y. Li, J. B. Jesus Lidon, N. K. Lincoln, S. R. Loss, R. Marichal, R. Matula, J. H. Moos, G. Moreno, A. Moron-Rios, B. Muys, J. Neirynck, L. Norgrove, M. Novo, V. Nuutinen, V. Nuzzo, M. Rahman P, J. Pansu, S. Paudel, G. Peres, L. Perez-Camacho, R. Pineiro, J.-F. Ponge, M. I. Rashid, S. Rebollo, J. Rodeiro-Iglesias, M. A. Rodriguez, A. M. Roth, G. X. Rousseau, A. Rozen, E. Sayad, L. van Schaik, B. C. Scharenbroch, M. Schirrmann, O. Schmidt, B. Schroder, J. Seeber, M. P. Shashkov, J. Singh, S. M. Smith, M. Steinwandter, J. A. Talavera, D. Trigo, J. Tsukamoto, A. W. de Valenca, S. J. Vanek, I. Virto, A. A. Wackett, M. W. Warren, N. H. Wehr, J. K. Whalen, M. B. Wironen, V. Wolters, I. V. Zenkova, W. Zhang, E. K. Cameron, N Eisenhauer. Erratum for the report “Global distribution of earthworm diversity. Science,  2020, 369(6503)
[50] 
Würtele, M.; Jelich-Ottmann, C.; Wittinghofer, A.; Oecking, C. Structural view of a fungal toxin acting on a 14-3-3 regulatory complex. EMBO J.,  2003, 22(5), 987-994.
[http://dx.doi.org/10.1093/emboj/cdg104] [PMID:  12606564] 
[51] 
Inoue, T.; Higuchi, Y.; Yoneyama, T.; Lin, B.; Nunomura, K.; Honma, Y.; Kato, N. Semisynthesis and biological evaluation of a cotylenin A mimic derived from fusicoccin A. Bioorg. Med. Chem. Lett.,  2018, 28(4), 646-650.
[http://dx.doi.org/10.1016/j.bmcl.2018.01.030] [PMID:  29398541] 
[52] 
Harmange Magnani, C.S.; Maimone, T.J. Fusicoccin keeps getting stickier: modulation of an adaptor protein interactome with a molecular glue leads to neurite outgrowth. Cell Chem. Biol.,  2020, 27(6), 635-637.
[http://dx.doi.org/10.1016/j.chembiol.2020.05.011] [PMID:  32559498] 
[53] 
Bartel, B.; Wünning, I.; Varshavsky, A. The recognition component of the N-end rule pathway. EMBO J.,  1990, 9(10), 3179-3189.
[http://dx.doi.org/10.1002/j.1460-2075.1990.tb07516.x] [PMID:  2209542] 
[54] 
Bachmair, A.; Finley, D.; Varshavsky, A. In vivo half-life of a protein is a function of its amino-terminal residue. Science,  1986, 234(4773), 179-186.
[http://dx.doi.org/10.1126/science.3018930] [PMID:  3018930] 
[55] 
Tasaki, T.; Mulder, L.C.; Iwamatsu, A.; Lee, M.J.; Davydov, I.V.; Varshavsky, A.; Muesing, M.; Kwon, Y.T. A family of mammalian E3 ubiquitin ligases that contain the UBR box motif and recognize N-degrons. Mol. Cell. Biol.,  2005, 25(16), 7120-7136.
[http://dx.doi.org/10.1128/MCB.25.16.7120-7136.2005] [PMID:  16055722] 
[56] 
Muday, G.K.; DeLong, A. Polar auxin transport: controlling where and how much. Trends Plant Sci.,  2001, 6(11), 535-542.
[http://dx.doi.org/10.1016/S1360-1385(01)02101-X] [PMID:  11701382] 
[57] 
Gray, W.M.; Kepinski, S.; Rouse, D.; Leyser, O.; Estelle, M. Auxin regulates SCF(TIR1)-dependent degradation of AUX/IAA proteins. Nature,  2001, 414(6861), 271-276.
[http://dx.doi.org/10.1038/35104500] [PMID:  11713520] 
[58] 
Skowyra, D.; Koepp, D.M.; Kamura, T.; Conrad, M.N.; Conaway, R.C.; Conaway, J.W.; Elledge, S.J.; Harper, J.W. Reconstitution of G1 cyclin ubiquitination with complexes containing SCFGrr1 and Rbx1. Science,  1999, 284(5414), 662-665.
[http://dx.doi.org/10.1126/science.284.5414.662] [PMID:  10213692] 
[59] 
Cardozo, T.; Pagano, M. The SCF ubiquitin ligase: insights into a molecular machine. Nat. Rev. Mol. Cell Biol.,  2004, 5(9), 739-751.
[http://dx.doi.org/10.1038/nrm1471] [PMID:  15340381] 
[60] 
Calderon-Villalobos, L.I.; Tan, X.; Zheng, N.; Estelle, M. Auxin perception-structural insights. Cold Spring Harb. Perspect. Biol.,  2010, 2(7)a005546
[http://dx.doi.org/10.1101/cshperspect.a005546] [PMID:  20504967] 
[61] 
Mogaki, R.; Okuro, K.; Ueki, R.; Sando, S.; Aida, T. Molecular glue that spatiotemporally turns on protein-protein interactions. J. Am. Chem. Soc.,  2019, 141(20), 8035-8040.
[http://dx.doi.org/10.1021/jacs.9b02427] [PMID:  30977371] 
[62] 
Goodson, H.V.; Jonasson, E.M. Microtubules and microtubule-associated proteins. Cold Spring Harb. Perspect. Biol.,  2018, 10(6)a022608
[http://dx.doi.org/10.1101/cshperspect.a022608] [PMID:  29858272] 
[63] 
Garzoni, M.; Okuro, K.; Ishii, N.; Aida, T.; Pavan, G.M. Structure and shape effects of molecular glue on supramolecular tubulin assemblies. ACS Nano,  2014, 8(1), 904-914.
[http://dx.doi.org/10.1021/nn405653k] [PMID:  24351029] 
[64] 
Huang, Q.; Li, F.; Liu, X.; Li, W.; Shi, W.; Liu, F.F.; O’Sullivan, B.; He, Z.; Peng, Y.; Tan, A.C.; Zhou, L.; Shen, J.; Han, G.; Wang, X.J.; Thorburn, J.; Thorburn, A.; Jimeno, A.; Raben, D.; Bedford, J.S.; Li, C.Y. Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat. Med.,  2011, 17(7), 860-866.
[http://dx.doi.org/10.1038/nm.2385] [PMID:  21725296] 
[65] 
Hentzen, N.B.; Mogaki, R.; Otake, S.; Okuro, K.; Aida, T. Intracellular photoactivation of caspase-3 by molecular glues for spatiotemporal apoptosis induction. J. Am. Chem. Soc.,  2020, 142(18), 8080-8084.
[http://dx.doi.org/10.1021/jacs.0c01823] [PMID:  32275408] 
[66] 
Zhou, Y.; Ye, H.; Chen, Y.; Zhu, R.; Yin, L. Photoresponsive drug/gene delivery systems. Biomacromolecules,  2018, 19(6), 1840-1857.
[http://dx.doi.org/10.1021/acs.biomac.8b00422] [PMID:  29701952] 
[67] 
Yang, G.; Wu, L.; Chen, G.; Jiang, M. Precise protein assembly of array structures. Chem. Commun. (Camb.),  2016, 52(70), 10595-10605.
[http://dx.doi.org/10.1039/C6CC04190F] [PMID:  27384233] 
[68] 
Luo, Q.; Hou, C.; Bai, Y.; Wang, R.; Liu, J. Protein assembly: versatile approaches to construct highly ordered nanostructures. Chem. Rev.,  2016, 116(22), 13571-13632.
[http://dx.doi.org/10.1021/acs.chemrev.6b00228] [PMID:  27587089] 
[69] 
Gordo, S.; Martos, V.; Santos, E.; Menéndez, M.; Bo, C.; Giralt, E.; de Mendoza, J. Stability and structural recovery of the tetramerization domain of p53-R337H mutant induced by a designed templating ligand. Proc. Natl. Acad. Sci. USA,  2008, 105(43), 16426-16431.
[http://dx.doi.org/10.1073/pnas.0805658105] [PMID:  18940924] 
[70] 
McGovern, R.E.; Fernandes, H.; Khan, A.R.; Power, N.P.; Crowley, P.B. Protein camouflage in cytochrome c-calixarene complexes. Nat. Chem.,  2012, 4(7), 527-533.
[http://dx.doi.org/10.1038/nchem.1342] [PMID:  22717436] 
[71] 
Renner, C.; Piehler, J.; Schrader, T. Arginine- and lysine-specific polymers for protein recognition and immobilization. J. Am. Chem. Soc.,  2006, 128(2), 620-628.
[http://dx.doi.org/10.1021/ja0560229] [PMID:  16402850] 
[72] 
Ingerman, L.A.; Cuellar, M.E.; Waters, M.L. A small molecule receptor that selectively recognizes trimethyl lysine in a histone peptide with native protein-like affinity. Chem. Commun. (Camb.),  2010, 46(11), 1839-1841.
[http://dx.doi.org/10.1039/C000255K] [PMID:  20198226] 
[73] 
McGovern, R.E.; McCarthy, A.A.; Crowley, P.B. Protein assembly mediated by sulfonatocalix[4]arene. Chem. Commun. (Camb.),  2014, 50(72), 10412-10415.
[http://dx.doi.org/10.1039/C4CC04897K] [PMID:  25068633] 
[74] 
McGovern, R.E.; Feifel, S.C.; Lisdat, F.; Crowley, P.B. Microscale crystals of cytochrome c and calixarene on electrodes: interprotein electron transfer between defined sites. Angew. Chem. Int. Ed. Engl.,  2015, 54(21), 6356-6359.
[http://dx.doi.org/10.1002/anie.201500191] [PMID:  25833222] 
[75] 
Matozaki, T.; Murata, Y.; Saito, Y.; Okazawa, H.; Ohnishi, H. Protein tyrosine phosphatase SHP-2: a proto-oncogene product that promotes Ras activation. Cancer Sci.,  2009, 100(10), 1786-1793.
[http://dx.doi.org/10.1111/j.1349-7006.2009.01257.x] [PMID:  19622105] 
[76] 
Chan, R.J.; Feng, G.S. PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase. Blood,  2007, 109(3), 862-867.
[http://dx.doi.org/10.1182/blood-2006-07-028829] [PMID:  17053061] 
[77] 
Chen, Y.N.; LaMarche, M.J.; Chan, H.M.; Fekkes, P.; Garcia-Fortanet, J.; Acker, M.G.; Antonakos, B.; Chen, C.H.; Chen, Z.; Cooke, V.G.; Dobson, J.R.; Deng, Z.; Fei, F.; Firestone, B.; Fodor, M.; Fridrich, C.; Gao, H.; Grunenfelder, D.; Hao, H.X.; Jacob, J.; Ho, S.; Hsiao, K.; Kang, Z.B.; Karki, R.; Kato, M.; Larrow, J.; La Bonte, L.R.; Lenoir, F.; Liu, G.; Liu, S.; Majumdar, D.; Meyer, M.J.; Palermo, M.; Perez, L.; Pu, M.; Price, E.; Quinn, C.; Shakya, S.; Shultz, M.D.; Slisz, J.; Venkatesan, K.; Wang, P.; Warmuth, M.; Williams, S.; Yang, G.; Yuan, J.; Zhang, J.H.; Zhu, P.; Ramsey, T.; Keen, N.J.; Sellers, W.R.; Stams, T.; Fortin, P.D. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature,  2016, 535(7610), 148-152.
[http://dx.doi.org/10.1038/nature18621] [PMID:  27362227] 
[78] 
Neel, B.G.; Chan, G.; Dhanji, S. Handbook of cell signaling,
	Second; Bradshaw, R.A.; Dennis, E.A., Eds.; Academic
	Press: San Diego, , 2010; 2, pp. 771-809.
[79] 
LaRochelle, J.R.; Fodor, M.; Vemulapalli, V.; Mohseni, M.; Wang, P.; Stams, T.; LaMarche, M.J.; Chopra, R.; Acker, M.G.; Blacklow, S.C. Structural reorganization of SHP2 by oncogenic mutations and implications for oncoprotein resistance to allosteric inhibition. Nat. Commun.,  2018, 9(1), 4508.
[http://dx.doi.org/10.1038/s41467-018-06823-9] [PMID:  30375388] 
[80] 
Pettersson, M.; Crews, C.M. PROteolysis targeting chimeras (PROTACs) - past, present and future. Drug Discov. Today. Technol.,  2019, 31, 15-27.
[http://dx.doi.org/10.1016/j.ddtec.2019.01.002] [PMID:  31200855] 
[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] 
Burslem, G.M.; Crews, C.M. Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell,  2020, 181(1), 102-114.
[http://dx.doi.org/10.1016/j.cell.2019.11.031] [PMID:  31955850] 
[83] 
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.
[http://dx.doi.org/10.1016/j.bmcl.2019.04.030] [PMID:  31047748] 
[84] 
Lamming, D.W. Inhibition of the mechanistic target of Rapamycin (mTOR)-Rapamycin and beyond. Cold Spring Harb. Perspect. Med.,  2016, 6(5)a025924
[http://dx.doi.org/10.1101/cshperspect.a025924] [PMID:  27048303] 
Cite As
Current Medicinal Chemistry

Targeted Protein Degradation and Regulation with Molecular Glue: Past and Recent Discoveries

Abstract
