PROTACs靶向蛋白质降解技术及其在合理药物设计中的应用
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摘要
近年来,合成蛋白水解靶向嵌合体(proteolysis targeting chimeric molecule,PROTAC)作为一种新颖的诱导蛋白降解策略引起了药物化学家们的广泛关注。这种双能嵌合分子通过连接体将靶蛋白配体与E3连接酶配体连接,招募E3至靶蛋白表面,引发多聚泛素化过程诱导蛋白降解。这种策略已经成功降解多种与人类疾病相关的蛋白质,并具有高效能、高选择性、以及靶向"不可成药"蛋白等优势。本文将重点介绍PROTACs技术的独特优势和研究进展,以及设计PROTAC分子时亟待解决的难题。
Recently,a new class of molecules has attracted the attention of pharmaceutical chemists,which is called proteolysis targeting chimeric molecules (PROTACs). These heterobifunctional molecules are designed to connect target protein ligand to E3 ligase ligand via a linker. By hijacking the E3 ligase,PROTACs facilitate substrate poly-ubiquitination and induce protein degradation. This strategy has been applied to a variety of proteins successfully and there are advantages of high efficacy,selectivity and ability to target "undruggable "proteins. We reviewed PROTAC technology from the unique advantages,recent progress and problems to be solved when we design PROTAC molecules.
Recently,a new class of molecules has attracted the attention of pharmaceutical chemists,which is called proteolysis targeting chimeric molecules (PROTACs). These heterobifunctional molecules are designed to connect target protein ligand to E3 ligase ligand via a linker. By hijacking the E3 ligase,PROTACs facilitate substrate poly-ubiquitination and induce protein degradation. This strategy has been applied to a variety of proteins successfully and there are advantages of high efficacy,selectivity and ability to target "undruggable "proteins. We reviewed PROTAC technology from the unique advantages,recent progress and problems to be solved when we design PROTAC molecules.
引文
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[7]CHURCHER I.Protac-Induced Protein Degradation in drug discovery:breaking the rules or just making new ones?[J].J Med Chem,2017,61(2):444-452.
[8]LU M,LIU T,JIAO Q,et al.Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway[J].Eur J Med Chem,2018,146:251-259.
[9]LU J,QIAN Y,ALTIERI M,et al.Hijacking the E3 bbiquitin ligase cereblon to efficiently target BRD4[J].Chem Biol,2015,22(6):755-763.
[10]BONDESON DP,MARES A,SMITH IED,et al.Catalytic in vivo protein knockdown by small-molecule PROTACs[J].Nat Chem Biol,2015,11(8):611-617.
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[19]SCHNEEKLOTH JS,FONSECA FN,KOLDOBSKIY M,et al.Chemical genetic control of protein levels:selective in vivo targeted degradation[J].J Am Chem Soc,2004,126(12):3748-3754.
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[26]DEMIZU Y,OKUHIRA K,MOTOI H,et al.Design and synthesis of estrogen receptor degradation inducer based on a protein knockdown strategy[J].Bioorg Med Chem Lett,2012,22(4):1793-1796.
[27]UMEZAWA H,AOYAGI T,SUDA H,et al.Bestatin,an inhibitor of aminopeptidase B,produced by actinomycetes[J].J Antibiot,1976,29(1):97-99.
[28]ITOH Y,ISHIKAWA M,KITAGUCHI R,et al.Double protein knockdown of c IAP1 and CRABP-II using a hybrid molecule consisting of ATRA and IAPs antagonist[J].Bioorg Med Chem Lett,2012,22(13):4453-4457.
[29]BUCKLEY DL,GUSTAFSON JL,MOLLE IV,et al.Small Molecule Inhibitors of the Interaction Between the E3 Ligase VHLand HIF1α[J].Angew Chem-Int Edit,2012,51(46):11463-11467.
[30]BUCKLEY DL,MOLLE IV,GAREISS PC,et al.Targeting the von Hippel-Lindau E3 Ubiquitin Ligase Using Small Molecules To Disrupt the VHL/HIF-1αInteraction[J].J Am Chem Soc,2012,134(10):4465-4468.
[31]JIANG Y,DENG Q,ZHAO H,et al.Development of stabilized peptide-based PROTACs against estrogen receptorα[J].Acs Chem Biol,2018,13(3):628-635.
[32]ITO T,ANDO H,SUZUKI T,et al.Identification of a primary target of thalidomide teratogenicity[J].Science,2010,327(5971):1345-1350.
[33]SCHIEDEL M,HERP D,HAMMELMANN S,et al.Chemically induced degradation of sirtuin 2(Sirt2)by a proteolysis targeting chimera(PROTAC)based on sirtuin rearranging ligands(SirReals)[J].J Med Chem,2018,61(2):482-491.
[34]ROBB CM,CONTRERAS JI,KOUR S,et al.Chemically induced degradation of CDK9 by a proteolysistargeting chimera(PROTAC)[J].Chem Commun,2017,53(54):7577-7580.
[35]CREW AP,RAINA K,DONG H,et al.Identification and characterization of von hippel-lindau-recruiting proteolysis targeting chimeras(PROTACs)of TANK-binding kinase 1[J].J Med Chem,2018,61(2):583-598.
[36]ZHOU B,HU J,XU F,et al.Discovery of a small-molecule degrader of bromodomain and extra-terminal(BET)proteins with picomolar cellular potencies and capable of achieving tumor regression[J].J Med Chem,2018,61(2):462-481.
[37]GAO N,CHEN Y,ZHAO Y,et al.Chemical methods to knock down the amyloid proteins[J].Molecules,2017,22(6):916-924.
[38]HENNING RK,VARGHESE JO,DAS S,et al.Degradation of Akt using protein-catalyzed capture agents[J].J Pept Sci,2016,22(4):196-200.
[39]CHU TT,GAO N,LI QQ,et al.Specific knockdown of endogenous Tau protein by peptide-directed ubiquitin-proteasome degradation[J].Cell Chem Biol,2016,23(4):453-461.
[40]LAI AC,TOURE M,HELLERSCHMIED D,et al.Modular PROTAC design for the degradation of oncogenic BCR-ABL[J].Angew Chem-Int Edit,2016,55(2):807-810.
[41]MONTROSE K,KRISSANSEN GW.Design of a PROTAC that antagonizes and destroys the cancer-forming X-protein of the hepatitis B virus[J].Biochem Bioph Res Co,2014,453(4):735-740.
[42]ZENGERLE M,CHAN K,CIULLI A.Selective small molecule induced degradation of the BET bromodomain protein BRD4[J].Acs Chem Biol,2015,10(8):1770-1777.
[43]LEE H,PUPPALA D,DR EYC,et al.Targeted degradation of the Aryl hydrocarbon receptor by the PROTAC approach:a useful chemical genetic tool[J].Chembiochem,2007,8(17):2058-2062.
[44]BUCKLEY DL,RAINA K,DARRICARRERE N,et al.HaloPROTACS:use of small molecule PROTACs to induce degradation of Halo Tag fusion proteins[J].Acs Chem Biol,2015,10(8):1831-1837.
[45]TOMOSHIGE S,NAITO M,HASHIMOTO Y,et al.Degradation of Halo Tag-fused nuclear proteins using bestatin-Halo Tag ligand hybrid molecules[J].Org Biomol Chem,2015,13(38):9746-9750.
[46]OHOKA N,NAGAI K,HATTORI T,et al.Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin proteasome pathway[J].Cell Death Dis,2014,5(11):e1513.
[47]ZHANG D,BAEK SH,HO A,et al.Degradation of target protein in living cells by small-molecule proteolysis inducer[J].Bioorg Med Chem Lett,2004,14(3):643-648.
[48]CYRUS K,WEHENKEL M,CHOI E,et al.Impact of linker length on the activity of PROTACs[J].Mol Biosyst,2011,7(2):359-364.
[49]CYRUS K,WEHENKEL M,CHOI EY.Jostling for Position:Optimizing Linker Location in the Design of Estrogen ReceptorTargeting PROTACs[J].Chem Med Chem,2010,5(7):979-985.
[2]PEER D,LIEBERMAN J.Special delivery:targeted therapy with small RNAs[J].Gene Ther,2011,18(12):1127-1133.
[3]CONG L,RAN FA,COX D,et al.Multiplex genome engineering using CRISPR/Cas systems[J].Trends Genet,2013,32(12):819-823.
[4]BOBBIN ML,ROSSI JJ.RNA interference(RNAi)-based therapeutics:delivering on the Promise?[J].Annu Rev Pharmacol Toxicol,2016,56(1):103-122.
[5]FEDOROV Y,ANDERSON EM,BIRMINGHAM A,et al.Offtarget effects by siRNA can induce toxic phenotype[J].RNA,2006,12(7):1188-1196.
[6]NEKLESA TK,WINKLER JD,CREWS CM.Targeted protein degradation by PROTACs[J].Pharmacol Therapeut,2017,174:138-144.
[7]CHURCHER I.Protac-Induced Protein Degradation in drug discovery:breaking the rules or just making new ones?[J].J Med Chem,2017,61(2):444-452.
[8]LU M,LIU T,JIAO Q,et al.Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway[J].Eur J Med Chem,2018,146:251-259.
[9]LU J,QIAN Y,ALTIERI M,et al.Hijacking the E3 bbiquitin ligase cereblon to efficiently target BRD4[J].Chem Biol,2015,22(6):755-763.
[10]BONDESON DP,MARES A,SMITH IED,et al.Catalytic in vivo protein knockdown by small-molecule PROTACs[J].Nat Chem Biol,2015,11(8):611-617.
[11]BONDESON DP,SMITH BE,BURSLEM GM,et al.Lessons in PROTAC design from selective degradation with a promiscuous warhead[J].Cell Chem Biol,2018,25(1):78-87.
[12]HSU HT,CHEN HM,YANG Z,et al.Phthalimide conjugation as a strategy for in vivo target protein degradation[J].Science,2015,348(6241):1372-1376.
[13]LAI AC,CREWS CM.Induced protein degradation:an emerging drug discovery paradigm[J].Nat Rev Drug Discov,2017,16(2):101-114.
[14]GOSINK MM,VIERSTRA RD.Redirecting the specificity of ubiquitination by modifying ubiquitin-conjugating enzymes[J].PNatl Acad Sci USA,1995,92(20):9117-9121.
[15]ZHOU P,BOGACKI R,MCREYNOLDS L,et al.Harnessing the ubiquitination machinery to target the degradation of specific cellular proteins[J].Mol Cell,2000,6(3):751-756.
[16]SAKAMOTO KM,DESHAIES RJ.Protacs:chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation[J].P Natl Acad Sci USA,2001,98(15):8554-8559.
[17]SAKAMOTO KM,KIM KB,VERMA R,et al.Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation[J].Mol Cell Proteomics,2003,2(12):1350-1358.
[18]IVAN M,KONDO K,YANG H,et al.HIFαTargeted for VHL-Mediated Destruction by Proline Hydroxylation:Implications for O2 Sensing[J].Science,2001,292(5516):464-468.
[19]SCHNEEKLOTH JS,FONSECA FN,KOLDOBSKIY M,et al.Chemical genetic control of protein levels:selective in vivo targeted degradation[J].J Am Chem Soc,2004,126(12):3748-3754.
[20]RODRIGUEZ-GONZALEZ A,CYRUS K,SALCIUS M,et al.Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer[J].Oncogene,2008,27(57):7201-7211.
[21]HINES J,GOUGH JD,CORSON TW,et al.Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phospho PROTACs[J].P Natl Acad Sci USA,2013,110(22):8942-8947.
[22]WILSON AJ,KERNS JK,CALLAHAN JF,et al.Keap calm,and carry on covalently[J].J Med Chem,2013,56(19):7463-7476.
[23]SMITH AR,PUCHEAULT M,TAE HS,et al.Targeted Intracellular Protein Degradation Induced by a Small Molecule:En Route to Chemical Proteomics[J].Bioorg Med Chem Lett,2008,18(22):5904-5908.
[24]ITOH Y,ISHIKAWA M,NAITO M,et al.Protein knockdown using methyl bestatin-ligand hybrid molecules:design and synthesis of inducers of ubiquitination-mediated degradation of cellular retinoic acid-binding proteins[J].J Am Chem Soc,2010,132(16):5820-5826.
[25]ITOH Y,KITAGUCHI R,ISHIKAWA M,et al.Design,synthesis and biological evaluation of nuclear receptor-degradation inducers[J].Bioorgan Med Chem,2011,19(22):6768-6778.
[26]DEMIZU Y,OKUHIRA K,MOTOI H,et al.Design and synthesis of estrogen receptor degradation inducer based on a protein knockdown strategy[J].Bioorg Med Chem Lett,2012,22(4):1793-1796.
[27]UMEZAWA H,AOYAGI T,SUDA H,et al.Bestatin,an inhibitor of aminopeptidase B,produced by actinomycetes[J].J Antibiot,1976,29(1):97-99.
[28]ITOH Y,ISHIKAWA M,KITAGUCHI R,et al.Double protein knockdown of c IAP1 and CRABP-II using a hybrid molecule consisting of ATRA and IAPs antagonist[J].Bioorg Med Chem Lett,2012,22(13):4453-4457.
[29]BUCKLEY DL,GUSTAFSON JL,MOLLE IV,et al.Small Molecule Inhibitors of the Interaction Between the E3 Ligase VHLand HIF1α[J].Angew Chem-Int Edit,2012,51(46):11463-11467.
[30]BUCKLEY DL,MOLLE IV,GAREISS PC,et al.Targeting the von Hippel-Lindau E3 Ubiquitin Ligase Using Small Molecules To Disrupt the VHL/HIF-1αInteraction[J].J Am Chem Soc,2012,134(10):4465-4468.
[31]JIANG Y,DENG Q,ZHAO H,et al.Development of stabilized peptide-based PROTACs against estrogen receptorα[J].Acs Chem Biol,2018,13(3):628-635.
[32]ITO T,ANDO H,SUZUKI T,et al.Identification of a primary target of thalidomide teratogenicity[J].Science,2010,327(5971):1345-1350.
[33]SCHIEDEL M,HERP D,HAMMELMANN S,et al.Chemically induced degradation of sirtuin 2(Sirt2)by a proteolysis targeting chimera(PROTAC)based on sirtuin rearranging ligands(SirReals)[J].J Med Chem,2018,61(2):482-491.
[34]ROBB CM,CONTRERAS JI,KOUR S,et al.Chemically induced degradation of CDK9 by a proteolysistargeting chimera(PROTAC)[J].Chem Commun,2017,53(54):7577-7580.
[35]CREW AP,RAINA K,DONG H,et al.Identification and characterization of von hippel-lindau-recruiting proteolysis targeting chimeras(PROTACs)of TANK-binding kinase 1[J].J Med Chem,2018,61(2):583-598.
[36]ZHOU B,HU J,XU F,et al.Discovery of a small-molecule degrader of bromodomain and extra-terminal(BET)proteins with picomolar cellular potencies and capable of achieving tumor regression[J].J Med Chem,2018,61(2):462-481.
[37]GAO N,CHEN Y,ZHAO Y,et al.Chemical methods to knock down the amyloid proteins[J].Molecules,2017,22(6):916-924.
[38]HENNING RK,VARGHESE JO,DAS S,et al.Degradation of Akt using protein-catalyzed capture agents[J].J Pept Sci,2016,22(4):196-200.
[39]CHU TT,GAO N,LI QQ,et al.Specific knockdown of endogenous Tau protein by peptide-directed ubiquitin-proteasome degradation[J].Cell Chem Biol,2016,23(4):453-461.
[40]LAI AC,TOURE M,HELLERSCHMIED D,et al.Modular PROTAC design for the degradation of oncogenic BCR-ABL[J].Angew Chem-Int Edit,2016,55(2):807-810.
[41]MONTROSE K,KRISSANSEN GW.Design of a PROTAC that antagonizes and destroys the cancer-forming X-protein of the hepatitis B virus[J].Biochem Bioph Res Co,2014,453(4):735-740.
[42]ZENGERLE M,CHAN K,CIULLI A.Selective small molecule induced degradation of the BET bromodomain protein BRD4[J].Acs Chem Biol,2015,10(8):1770-1777.
[43]LEE H,PUPPALA D,DR EYC,et al.Targeted degradation of the Aryl hydrocarbon receptor by the PROTAC approach:a useful chemical genetic tool[J].Chembiochem,2007,8(17):2058-2062.
[44]BUCKLEY DL,RAINA K,DARRICARRERE N,et al.HaloPROTACS:use of small molecule PROTACs to induce degradation of Halo Tag fusion proteins[J].Acs Chem Biol,2015,10(8):1831-1837.
[45]TOMOSHIGE S,NAITO M,HASHIMOTO Y,et al.Degradation of Halo Tag-fused nuclear proteins using bestatin-Halo Tag ligand hybrid molecules[J].Org Biomol Chem,2015,13(38):9746-9750.
[46]OHOKA N,NAGAI K,HATTORI T,et al.Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin proteasome pathway[J].Cell Death Dis,2014,5(11):e1513.
[47]ZHANG D,BAEK SH,HO A,et al.Degradation of target protein in living cells by small-molecule proteolysis inducer[J].Bioorg Med Chem Lett,2004,14(3):643-648.
[48]CYRUS K,WEHENKEL M,CHOI E,et al.Impact of linker length on the activity of PROTACs[J].Mol Biosyst,2011,7(2):359-364.
[49]CYRUS K,WEHENKEL M,CHOI EY.Jostling for Position:Optimizing Linker Location in the Design of Estrogen ReceptorTargeting PROTACs[J].Chem Med Chem,2010,5(7):979-985.