蛋白降解靶向嵌合体(PROTAC)的研究进展
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摘要
蛋白降解靶向嵌合体(proteolytic targeting chimera,PROTAC)是一类能够通过诱导靶蛋白的多聚泛素化而导致靶蛋白降解的化合物。PROTAC作为双功能分子,具有非常广泛的应用与发展空间。PROTAC是药物研发领域的一个新兴方向,通过降解靶蛋白来调控体内蛋白含量的策略极大地拓展了潜在药物靶标的范围。本文主要简介PROTAC的结构、作用机制、最新研究成果、技术优势以及目前存在的问题。
Proteolysis targeting chimera(PROTAC) are a class of compounds which can induce the poly-ubiquitination of the target proteins and promote their degradation.As a bifunctional molecule,RPOTAC has a wide range of space for application and development.PROTAC is a new direction in the field of drug discovery,and the strategy of regulating protein content in vivo by degrading target proteins greatly expands the range of potential drug targets.In this paper,the structure,mechanism,latest research results,technical advantages and disadvantages of PROTAC were introduced.
Proteolysis targeting chimera(PROTAC) are a class of compounds which can induce the poly-ubiquitination of the target proteins and promote their degradation.As a bifunctional molecule,RPOTAC has a wide range of space for application and development.PROTAC is a new direction in the field of drug discovery,and the strategy of regulating protein content in vivo by degrading target proteins greatly expands the range of potential drug targets.In this paper,the structure,mechanism,latest research results,technical advantages and disadvantages of PROTAC were introduced.
引文
[1] NEKLESA T K,WINKLER J D,CREWS C M.Targeted protein degradation by PROTACs[J].Pharmacol Ther,2017,174(6):138-144.
[2] WEISSMAN A M,SHABEK N,CIECHANOVER A.The predator becomes the prey:regulating the ubiquitin system by ubiquitylation and degradation[J].Nat Rev Mol Cell Biol,2011,12(9):605-620.
[3] PICKART C M.Mechanisms underlying ubiquitination[J].Annu Rev Biochem,2001,70(70):503-533.
[4] SPASSER L,BRIK A.Chemistry and biology of the ubiquitin signal[J].Angew Chem(Int Ed Engl),2012,51(28):6840-6862.
[5] CIECHANOVER A.Proteolysis:from the lysosome to ubiquitin and the proteasome[J].Nat Rev Mol Cell Biol,2005,6(1):79-87.
[6] LAI A C,CREWS C M.Induced protein degradation:an emerging drug discovery paradigm[J].Nat Rev Drug Discov,2017,16(2):101-114.
[7] BULATOV E,CIULLI A.Targeting Cullin-RING E3 ubiquitin ligases for drug discovery:structure,assembly and small-molecule modulation[J].Biochem J,2015,467(3):365-386.
[8] CORSON T W,ABERLE N,CREWS C M.Design and applications of bifunctional small molecules:why two heads are better than one[J].ACS Chem Biol,2008,3(11):677-692.
[9] SAKAMOTO K M,KIM K B,KUMAGAI A,et al.PROTACs:chimeric molecules that target proteins to the skp1-cullin-f box complex for ubiquitination and degradation[J].Proc Natl Acad Sci USA,2001,98(15):8554-8559.
[10] HINES J,GOUGH J D,CORSON T W,et al.Post-translational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs[J].Proc Natl Acad Sci USA,2013,110(22):8942-8947.
[11] TOURE M,CREWS C M.Small-molecule PROTACs:new approaches to protein degradation[J].Angew Chem(Int Ed Engl),2016,55(6):1966-1973.
[12] OHOKA N,SHIBATA N,HATTORI T,et al.Protein knockdown technology:application of ubiquitin ligase to cancer therapy[J].Curr Cancer Drug Tar,2015,16(2):136-146.
[13] VASSILEV L T,VU B T,GRAVES B,et al.In-vivo activation of the p53 pathway by small-molecule antagonists of MDM2[J].Science,2004,303(5659):844-848.
[14] 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.
[15] JING L,QIAN Y,ALTIERI M,et al.Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4[J].Chem Biol,2015,22(6):755-763.
[16] WINTER G E,BUCKLEY D L,PAULK J,et al.Phthalimide conjugation as a strategy for in vivo target protein degradation[J].Science,2015,348(6241):1376-1381.
[17] 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.
[18] BURSLEM G M,SMITH B E,LAI A C,et al.The advantages of targeted protein degradation over inhibition:an RTK case study[J].Cell Chem Biol,2018,25(1) :67-77.
[19] ZHANG C,HAN X R,YANG X,et al.Proteolysis targeting chimeras(PROTACs) of anaplastic lymphoma kinase(ALK)[J].Eur J Med Chem,2018,151:304-314.
[20] HATCHER J M,WANG E,JOHANNESSEN L,et al.Development of highly potent and selective steroidal inhibitors and degraders of CDK8[J].ACS Med Chem Lett,2018,9(6):540-545.
[21] OLSON C M,JIANG B,ERB M A,et al.Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation[J].Nat Chem Biol,2017,14(2):163-170.
[22] ROBB C M,CONTRERAS J I,KOUR S,et al.Catalytic in vivo protein knockdown by small-molecule PROTACs[J].Nat Chem Biol,2015,11(8):611-617.
[23] BONDESON D P,MARES A,SMITH I E,et al.Selective small molecule induced degradation of the BET bromodomain protein BRD4[J].ACS Chem Biol,2015,10(8):1770-1777.
[24] SHIBATA N,NAGAI K,MORITA Y,et al.Deve-lopment of protein degradation inducers of androgen receptor by conjugation of androgen receptor ligands and inhibitor of apoptosis protein(IAP) ligands[J].J Med Chem,2017,61(2):543-575.
[25] LEBRAUD H,WRIGHT D J,JOHNSON C N,et al.Protein degradation by in-cell self-assembly of proteolysis targeting chimeras[J].ACS Central Sci,2016,2(12):927-934.
[26] BONDESON D P,MARES A,SMITH I E,et al.Catalytic in vivo protein knockdown by small-molecule PROTACs[J].Nat Chem Biol,2015,11(8):611-617.
[2] WEISSMAN A M,SHABEK N,CIECHANOVER A.The predator becomes the prey:regulating the ubiquitin system by ubiquitylation and degradation[J].Nat Rev Mol Cell Biol,2011,12(9):605-620.
[3] PICKART C M.Mechanisms underlying ubiquitination[J].Annu Rev Biochem,2001,70(70):503-533.
[4] SPASSER L,BRIK A.Chemistry and biology of the ubiquitin signal[J].Angew Chem(Int Ed Engl),2012,51(28):6840-6862.
[5] CIECHANOVER A.Proteolysis:from the lysosome to ubiquitin and the proteasome[J].Nat Rev Mol Cell Biol,2005,6(1):79-87.
[6] LAI A C,CREWS C M.Induced protein degradation:an emerging drug discovery paradigm[J].Nat Rev Drug Discov,2017,16(2):101-114.
[7] BULATOV E,CIULLI A.Targeting Cullin-RING E3 ubiquitin ligases for drug discovery:structure,assembly and small-molecule modulation[J].Biochem J,2015,467(3):365-386.
[8] CORSON T W,ABERLE N,CREWS C M.Design and applications of bifunctional small molecules:why two heads are better than one[J].ACS Chem Biol,2008,3(11):677-692.
[9] SAKAMOTO K M,KIM K B,KUMAGAI A,et al.PROTACs:chimeric molecules that target proteins to the skp1-cullin-f box complex for ubiquitination and degradation[J].Proc Natl Acad Sci USA,2001,98(15):8554-8559.
[10] HINES J,GOUGH J D,CORSON T W,et al.Post-translational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs[J].Proc Natl Acad Sci USA,2013,110(22):8942-8947.
[11] TOURE M,CREWS C M.Small-molecule PROTACs:new approaches to protein degradation[J].Angew Chem(Int Ed Engl),2016,55(6):1966-1973.
[12] OHOKA N,SHIBATA N,HATTORI T,et al.Protein knockdown technology:application of ubiquitin ligase to cancer therapy[J].Curr Cancer Drug Tar,2015,16(2):136-146.
[13] VASSILEV L T,VU B T,GRAVES B,et al.In-vivo activation of the p53 pathway by small-molecule antagonists of MDM2[J].Science,2004,303(5659):844-848.
[14] 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.
[15] JING L,QIAN Y,ALTIERI M,et al.Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4[J].Chem Biol,2015,22(6):755-763.
[16] WINTER G E,BUCKLEY D L,PAULK J,et al.Phthalimide conjugation as a strategy for in vivo target protein degradation[J].Science,2015,348(6241):1376-1381.
[17] 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.
[18] BURSLEM G M,SMITH B E,LAI A C,et al.The advantages of targeted protein degradation over inhibition:an RTK case study[J].Cell Chem Biol,2018,25(1) :67-77.
[19] ZHANG C,HAN X R,YANG X,et al.Proteolysis targeting chimeras(PROTACs) of anaplastic lymphoma kinase(ALK)[J].Eur J Med Chem,2018,151:304-314.
[20] HATCHER J M,WANG E,JOHANNESSEN L,et al.Development of highly potent and selective steroidal inhibitors and degraders of CDK8[J].ACS Med Chem Lett,2018,9(6):540-545.
[21] OLSON C M,JIANG B,ERB M A,et al.Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation[J].Nat Chem Biol,2017,14(2):163-170.
[22] ROBB C M,CONTRERAS J I,KOUR S,et al.Catalytic in vivo protein knockdown by small-molecule PROTACs[J].Nat Chem Biol,2015,11(8):611-617.
[23] BONDESON D P,MARES A,SMITH I E,et al.Selective small molecule induced degradation of the BET bromodomain protein BRD4[J].ACS Chem Biol,2015,10(8):1770-1777.
[24] SHIBATA N,NAGAI K,MORITA Y,et al.Deve-lopment of protein degradation inducers of androgen receptor by conjugation of androgen receptor ligands and inhibitor of apoptosis protein(IAP) ligands[J].J Med Chem,2017,61(2):543-575.
[25] LEBRAUD H,WRIGHT D J,JOHNSON C N,et al.Protein degradation by in-cell self-assembly of proteolysis targeting chimeras[J].ACS Central Sci,2016,2(12):927-934.
[26] BONDESON D P,MARES A,SMITH I E,et al.Catalytic in vivo protein knockdown by small-molecule PROTACs[J].Nat Chem Biol,2015,11(8):611-617.