组蛋白乙酰转移酶p300/CBP抑制剂的研究进展
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摘要
由高度同源的腺病毒E1A相关的300 kDa蛋白(p300)和环磷酸腺苷反应元件结合蛋白(CREB)的结合蛋白(CBP)组成的p300/CBP家族是组蛋白乙酰转移酶(HAT)家族主要成员之一。p300/CBP参与细胞周期进展和细胞的生长、分化和发展,是一类非常重要的辅激活因子,可以调节多种关键转录调节因子的功能。p300/CBP与多种肿瘤疾病密切相关,是一个极具应用前景的肿瘤治疗靶标。综述p300/CBP抑制剂的研究进展,旨在为开发新型选择性p300/CBP抑制剂提供参考。
The p300/CBP family consisting of the highly homologous adenovirus E1 A-associated 300 kDa protein(p300) and CREB(cAMP responsive element binding protein) binding protein(CBP) is one of the major members of the histone acetyltransferases families(HAT).Acting as a very important coactivator that can regulate the functions of key transcription regulatory factors, p300/CBP is involved in cell cycle progression as well as cell growth, differentiation and development. Since p300/CBP is also closely related to a variety of tumors, it emerges as a promising target for tumor therapy. This paper reviewed the research progress of p300/CBP inhibitors in order to provide reference for the development of novel selective p300/CBP inhibitors.
The p300/CBP family consisting of the highly homologous adenovirus E1 A-associated 300 kDa protein(p300) and CREB(cAMP responsive element binding protein) binding protein(CBP) is one of the major members of the histone acetyltransferases families(HAT).Acting as a very important coactivator that can regulate the functions of key transcription regulatory factors, p300/CBP is involved in cell cycle progression as well as cell growth, differentiation and development. Since p300/CBP is also closely related to a variety of tumors, it emerges as a promising target for tumor therapy. This paper reviewed the research progress of p300/CBP inhibitors in order to provide reference for the development of novel selective p300/CBP inhibitors.
引文
[1]Roth S Y,Denu J M,Allis C D.Histone acetyltransferase[J].Annu Rev Biochem,2001,70:81-120.
[2]Balasubramanyam K,Altaf M,Varier R A,et al.Polyisoprenylated benzophenone,garcinol,a natural histone acetyltransferase inhibitor,represses chromatin transcription and alters global gene expression[J].JBiol Chem,2004,279(32):33716-33726.
[3]Goodman R H,Smolik S.CBP/p300 in cell growth,transformation,and development[J].Genes Dev,2000,14(13):1553-1577.
[4]Bedford D C,Kasper L H,Fukuyama T,et al.Target gene context influences the transcriptional requirement for the KAT3 family of CBPand p300 histone acetyltransferases[J].Epigenetics,2010,5(1):9-15.
[5]Hay D A,Fedorov O,Martin S,et al.Discovery and optimization of small-molecule ligands for the CBP/p300 bromodomains[J].J Am Chem Soc,2014,136(26):9308-9319.
[6]Wang F,Marshall C B,Ikura M.Transcriptional/epigenetic regulator CBP/p300 in tumorigenesis:structural and functional versatility in target recognition[J].Cell Mol Life Sci,2013,70(21):3989-4008.
[7]Dyson H J,Wright P E.Intrinsically unstructured proteins and their functions[J].Nat Rev Mol Cell Biol,2005,6(3):197-208.
[8]Bedford D C,Brindle P K.Is histone acetylation the most important physiological function for CBP and p300?[J].Aging(Albany NY),2012,4(4):247-255.
[9]Romero F A,Taylor A M,Crawford T D,et al.Disrupting acetyl-lysine recognition:progress in the development of bromodomain inhibitors[J].J Med Chem,2016,59(4):1271-1298.
[10]Fan S,Ma Y X,Wang C.p300 modulates the BRCA1 inhibition of estrogen receptor activity[J].Cancer Res,2002,62(1):141-151.
[11]Bandyopadhyay D,Okan N A,Bales E,et al.Down-regulation of p300/CBP histone acetyltransferase activates a senescence checkpoint in human melanocytes[J].Cancer Res,2002,62(21):6231-6239.
[12]Li M,Luo R Z,Chen J W,et al.High expression of transcriptional coactivator p300 correlates with aggressive features and poor prognosis of hepatocellular carcinoma[J].J Transl Med,2011,9(1):5.Doi:10.1186/1479-5876-9-5.
[13]Gao Y,Geng J,Hong X,et al.Expression of p300 and CBP is associated with poor prognosis in small cell lung cancer[J].Int J Clin Exp Pathol,2014,7(2):760-767.
[14]Ishihama K,Yamakawa M,Semba S,et al.Expression of HDAC1 and CBP/p300 in human colorectal carcinomas[J].J Clin Pathol,2007,60(11):1205-1210.
[15]Hou X,Li Y,Luo R Z,et al.High expression of the transcriptional coactivator p300 predicts poor survival in resectable non-small cell lung cancers[J].Eur J Surg Oncol,2012,38(6):523-530.
[16]Xiao X S,Cai M Y,Chen J W,et al.High expression of p300 in human breast cancer correlates with tumor recurrence and predicts adverse prognosis[J].Chin J Cancer Res,2011,23(3):201-207.
[17]Yokomizo C,Yamaguchi K,Itoh Y,et al.High expression of p300 in HCC predicts shortened overall survival in association with enhanced epithelial mesenchymal transition of HCC cells[J].Cancer Lett,2011,310(2):140-147.
[18]Jin L,Garcia J,Chan E,et al.Therapeutic targeting of the CBP/p300 bromodomain blocks the growth of castration-resistant prostate cancer[J].Cancer Res,2017,77(20):5564-5575.
[19]Pasqualucci L,Dominguez-Sola D,Chiarenza A,et al.Inactivating mutations of acetyltransferase genes in B-cell lymphoma[J].Nature,2011,471(7337):189-195.
[20]Mullighan C G,Zhang J,Kasper L H,et al.CREBBP mutations in relapsed acute lymphoblastic leukaemia[J].Nature,2011,471(7337):235-239.
[21]Holmfeldt L,Wei L,Diaz-Flores E,et al.The genomic landscape of hypodiploid acute lymphoblastic leukemia[J].Nat Genet,2013,45(3):242-252.
[22]Giotopoulos G,Chan W I,Horton S J,et al.The epigenetic regulators CBP and p300 facilitate leukemogenesis and represent therapeutic targets in acute myeloid leukemia[J].Oncogene,2016,35(3):279-289.
[23]Picaud S,Fedorov O,Thanasopoulou A,et al.Generation of a selective small molecule inhibitor of the CBP/p300 bromodomain for leukemia therapy[J].Cancer Res,2015,75(23):5106-5119.
[24]Sachchidanand,Resnick-Silverman L,Yan S,et al.Target structurebased discovery of small molecules that block human p53 and CREBbinding protein association[J].Chem Biol,2006,13(1):81-90.
[25]Borah J C,Mujtaba S,Karakikes I,et al.A small molecule binding to the coactivator CREB-binding protein blocks apoptosis in cardiomyocytes[J].Chem Biol,2011,18(4):531-541.
[26]Hewings D S,Wang M,Philpott M,et al.3,5-dimethylisoxazoles act as acetyl-lysine-mimetic bromodomain ligands[J].J Med Chem,2011,54(19):6761-6770.
[27]Rooney T P,Filippakopoulos P,Fedorov O,et al.A series of potent CREBBP bromodomain ligands reveals an induced-fit pocket stabilized by a cation-pi interaction[J].Angew Chem Int Ed Engl,2014,53(24):6126-6130.
[28]Xu M,Unzue A,Dong J,et al.Discovery of CREBBP bromodomain inhibitors by high-throughput docking and hit optimization guided by molecular dynamics[J].J Med Chem,2015,59(4):1340-1349.
[29]Unzue A,Xu M,Dong J,et al.Fragment-based design of selective nanomolar ligands of the CREBBP bromodomain[J].J Med Chem,2016,59(4):1350-1356.
[30]Hay D,Fedorov O,Filippakopoulos P,et al.The design and synthesis of 5-and 6-isoxazolylbenzimidazoles as selective inhibitors of the BETbromodomains[J].Medchemcomm,2013,4(1):140-144.
[31]Denny R A,Flick A C,Coe J,et al.Structure-based design of highly selective inhibitors of the CREB binding protein bromodomain[J].JMed Chem,2017,60(13):5349-5363.
[32]Popp T A,Tallant C,Rogers C,et al.Development of selective CBP/P300 benzoxazepine bromodomain inhibitors[J].J Med Chem,2016,59(19):8889-8912.
[33]Anthony P N,Adrien T D M,Richaed B,et al.Isoxazolyl substituted imidazopyridines:WO,2016/170323 A1[P].2016-10-27.
[34]Anthony P N,Adrien T D M,Thomas O S,et al.Isoxazolyl substituted benzimidazoles:WO,2016/170324 A1[P].2016-10-27.
[35]Anthony P N,Adrien T D M,Thomas O S,et al.Pharmaceutical compounds:WO,2018/073586 A1[P].2018-04-26.
[36]Anthony P N,Adrien T D M,Jonathan S,et al.Pharmaceutical compounds:WO,2018/073587 A1[P].2018-04-26.
[37]Taylor A M,C?téA,Hewitt M C,et al.Fragment-based discovery of a selective and cell-active benzodiazepinone CBP/EP300 bromodomain inhibitor(CPI-637)[J].ACS Med Chem Lett,2016,7(5):531-536.
[38]Crawford T D,Romero F A,Lai K W,et al.Discovery of a potent and selective in vivo probe(GNE-272)for the bromodomains of CBP/EP300[J].J Med Chem,2016,59(23):10549-10563.
[39]Romero F A,Murray J,Lai K W,et al.GNE-781,a highly advanced potent and selective bromodomain inhibitor of cyclic adenosine monophosphate response element binding protein,binding protein(CBP)[J].J Med Chem,2017,60(22):9162-9183.
[40]Lai K W,Romero F A,Tsui V,et al.Design and synthesis of a biaryl series as inhibitors for the bromodomains of CBP/P300[J].Bioorg Med Chem Lett,2018,28(1):15-23.
[41]Lau O D,Kundu T K,Soccio R E.HATs off:selective synthetic inhibitors of the histone acetyltransferases p300 and PCAF[J].Mol Cell,2000,5(3):589-595.
[42]Balasubramanyam K,Swaminathan V,Ranganathan A,et al.Small molecule modulators of histone acetyltransferase p300[J].J Biol Chem,2003,278(21):19134-19140.
[43]Balasubramanyam K,Varier R A,Altaf M,et al.Curcumin,a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase,represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription[J].J Biol Chem,2004,279(49):51163-51171.
[44]Arif M,Pradhan S K,Thanuia G R.Mechanism of p300 specific histone acetyltransferase inhibition by small molecules[J].J Med Chem,2009,52(2):267-277.
[45]Mantelingu K,Reddy B A,Swaminathan V,et al.Specific inhibition of p300-HAT alters global gene expression and represses HIVreplication[J].Chem Biol,2007,14(6):645-657.
[46]Bowers E M,Yan G,Mukherjee C,et al.Virtual ligand screening of the p300/CBP histone acetyltransferase:identification of a selective small molecule inhibitor[J].Chem Biol,2010,17(5):471-482.
[47]Shrimp J H,Sorum A W,Garlick J M,et al.Characterizing the covalent targets of a small molecule inhibitor of the lysine acetyltransferase P300[J].ACS Med Chem Lett,2016,7(2):151-155.
[48]Lasko L M,Jakob C G,Edalji R P,et al.Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours[J].Nature,2017,550(7674):128-132.
[49]Michaelides M R,Kluge A,Patane M,et al.Discovery of spiro oxazolidinediones as selective,orally bioavailable inhibitors of p300/CBPhistone acetyltransferases[J].ACS Med Chem Lett,2018,9(1):28-33.
[2]Balasubramanyam K,Altaf M,Varier R A,et al.Polyisoprenylated benzophenone,garcinol,a natural histone acetyltransferase inhibitor,represses chromatin transcription and alters global gene expression[J].JBiol Chem,2004,279(32):33716-33726.
[3]Goodman R H,Smolik S.CBP/p300 in cell growth,transformation,and development[J].Genes Dev,2000,14(13):1553-1577.
[4]Bedford D C,Kasper L H,Fukuyama T,et al.Target gene context influences the transcriptional requirement for the KAT3 family of CBPand p300 histone acetyltransferases[J].Epigenetics,2010,5(1):9-15.
[5]Hay D A,Fedorov O,Martin S,et al.Discovery and optimization of small-molecule ligands for the CBP/p300 bromodomains[J].J Am Chem Soc,2014,136(26):9308-9319.
[6]Wang F,Marshall C B,Ikura M.Transcriptional/epigenetic regulator CBP/p300 in tumorigenesis:structural and functional versatility in target recognition[J].Cell Mol Life Sci,2013,70(21):3989-4008.
[7]Dyson H J,Wright P E.Intrinsically unstructured proteins and their functions[J].Nat Rev Mol Cell Biol,2005,6(3):197-208.
[8]Bedford D C,Brindle P K.Is histone acetylation the most important physiological function for CBP and p300?[J].Aging(Albany NY),2012,4(4):247-255.
[9]Romero F A,Taylor A M,Crawford T D,et al.Disrupting acetyl-lysine recognition:progress in the development of bromodomain inhibitors[J].J Med Chem,2016,59(4):1271-1298.
[10]Fan S,Ma Y X,Wang C.p300 modulates the BRCA1 inhibition of estrogen receptor activity[J].Cancer Res,2002,62(1):141-151.
[11]Bandyopadhyay D,Okan N A,Bales E,et al.Down-regulation of p300/CBP histone acetyltransferase activates a senescence checkpoint in human melanocytes[J].Cancer Res,2002,62(21):6231-6239.
[12]Li M,Luo R Z,Chen J W,et al.High expression of transcriptional coactivator p300 correlates with aggressive features and poor prognosis of hepatocellular carcinoma[J].J Transl Med,2011,9(1):5.Doi:10.1186/1479-5876-9-5.
[13]Gao Y,Geng J,Hong X,et al.Expression of p300 and CBP is associated with poor prognosis in small cell lung cancer[J].Int J Clin Exp Pathol,2014,7(2):760-767.
[14]Ishihama K,Yamakawa M,Semba S,et al.Expression of HDAC1 and CBP/p300 in human colorectal carcinomas[J].J Clin Pathol,2007,60(11):1205-1210.
[15]Hou X,Li Y,Luo R Z,et al.High expression of the transcriptional coactivator p300 predicts poor survival in resectable non-small cell lung cancers[J].Eur J Surg Oncol,2012,38(6):523-530.
[16]Xiao X S,Cai M Y,Chen J W,et al.High expression of p300 in human breast cancer correlates with tumor recurrence and predicts adverse prognosis[J].Chin J Cancer Res,2011,23(3):201-207.
[17]Yokomizo C,Yamaguchi K,Itoh Y,et al.High expression of p300 in HCC predicts shortened overall survival in association with enhanced epithelial mesenchymal transition of HCC cells[J].Cancer Lett,2011,310(2):140-147.
[18]Jin L,Garcia J,Chan E,et al.Therapeutic targeting of the CBP/p300 bromodomain blocks the growth of castration-resistant prostate cancer[J].Cancer Res,2017,77(20):5564-5575.
[19]Pasqualucci L,Dominguez-Sola D,Chiarenza A,et al.Inactivating mutations of acetyltransferase genes in B-cell lymphoma[J].Nature,2011,471(7337):189-195.
[20]Mullighan C G,Zhang J,Kasper L H,et al.CREBBP mutations in relapsed acute lymphoblastic leukaemia[J].Nature,2011,471(7337):235-239.
[21]Holmfeldt L,Wei L,Diaz-Flores E,et al.The genomic landscape of hypodiploid acute lymphoblastic leukemia[J].Nat Genet,2013,45(3):242-252.
[22]Giotopoulos G,Chan W I,Horton S J,et al.The epigenetic regulators CBP and p300 facilitate leukemogenesis and represent therapeutic targets in acute myeloid leukemia[J].Oncogene,2016,35(3):279-289.
[23]Picaud S,Fedorov O,Thanasopoulou A,et al.Generation of a selective small molecule inhibitor of the CBP/p300 bromodomain for leukemia therapy[J].Cancer Res,2015,75(23):5106-5119.
[24]Sachchidanand,Resnick-Silverman L,Yan S,et al.Target structurebased discovery of small molecules that block human p53 and CREBbinding protein association[J].Chem Biol,2006,13(1):81-90.
[25]Borah J C,Mujtaba S,Karakikes I,et al.A small molecule binding to the coactivator CREB-binding protein blocks apoptosis in cardiomyocytes[J].Chem Biol,2011,18(4):531-541.
[26]Hewings D S,Wang M,Philpott M,et al.3,5-dimethylisoxazoles act as acetyl-lysine-mimetic bromodomain ligands[J].J Med Chem,2011,54(19):6761-6770.
[27]Rooney T P,Filippakopoulos P,Fedorov O,et al.A series of potent CREBBP bromodomain ligands reveals an induced-fit pocket stabilized by a cation-pi interaction[J].Angew Chem Int Ed Engl,2014,53(24):6126-6130.
[28]Xu M,Unzue A,Dong J,et al.Discovery of CREBBP bromodomain inhibitors by high-throughput docking and hit optimization guided by molecular dynamics[J].J Med Chem,2015,59(4):1340-1349.
[29]Unzue A,Xu M,Dong J,et al.Fragment-based design of selective nanomolar ligands of the CREBBP bromodomain[J].J Med Chem,2016,59(4):1350-1356.
[30]Hay D,Fedorov O,Filippakopoulos P,et al.The design and synthesis of 5-and 6-isoxazolylbenzimidazoles as selective inhibitors of the BETbromodomains[J].Medchemcomm,2013,4(1):140-144.
[31]Denny R A,Flick A C,Coe J,et al.Structure-based design of highly selective inhibitors of the CREB binding protein bromodomain[J].JMed Chem,2017,60(13):5349-5363.
[32]Popp T A,Tallant C,Rogers C,et al.Development of selective CBP/P300 benzoxazepine bromodomain inhibitors[J].J Med Chem,2016,59(19):8889-8912.
[33]Anthony P N,Adrien T D M,Richaed B,et al.Isoxazolyl substituted imidazopyridines:WO,2016/170323 A1[P].2016-10-27.
[34]Anthony P N,Adrien T D M,Thomas O S,et al.Isoxazolyl substituted benzimidazoles:WO,2016/170324 A1[P].2016-10-27.
[35]Anthony P N,Adrien T D M,Thomas O S,et al.Pharmaceutical compounds:WO,2018/073586 A1[P].2018-04-26.
[36]Anthony P N,Adrien T D M,Jonathan S,et al.Pharmaceutical compounds:WO,2018/073587 A1[P].2018-04-26.
[37]Taylor A M,C?téA,Hewitt M C,et al.Fragment-based discovery of a selective and cell-active benzodiazepinone CBP/EP300 bromodomain inhibitor(CPI-637)[J].ACS Med Chem Lett,2016,7(5):531-536.
[38]Crawford T D,Romero F A,Lai K W,et al.Discovery of a potent and selective in vivo probe(GNE-272)for the bromodomains of CBP/EP300[J].J Med Chem,2016,59(23):10549-10563.
[39]Romero F A,Murray J,Lai K W,et al.GNE-781,a highly advanced potent and selective bromodomain inhibitor of cyclic adenosine monophosphate response element binding protein,binding protein(CBP)[J].J Med Chem,2017,60(22):9162-9183.
[40]Lai K W,Romero F A,Tsui V,et al.Design and synthesis of a biaryl series as inhibitors for the bromodomains of CBP/P300[J].Bioorg Med Chem Lett,2018,28(1):15-23.
[41]Lau O D,Kundu T K,Soccio R E.HATs off:selective synthetic inhibitors of the histone acetyltransferases p300 and PCAF[J].Mol Cell,2000,5(3):589-595.
[42]Balasubramanyam K,Swaminathan V,Ranganathan A,et al.Small molecule modulators of histone acetyltransferase p300[J].J Biol Chem,2003,278(21):19134-19140.
[43]Balasubramanyam K,Varier R A,Altaf M,et al.Curcumin,a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase,represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription[J].J Biol Chem,2004,279(49):51163-51171.
[44]Arif M,Pradhan S K,Thanuia G R.Mechanism of p300 specific histone acetyltransferase inhibition by small molecules[J].J Med Chem,2009,52(2):267-277.
[45]Mantelingu K,Reddy B A,Swaminathan V,et al.Specific inhibition of p300-HAT alters global gene expression and represses HIVreplication[J].Chem Biol,2007,14(6):645-657.
[46]Bowers E M,Yan G,Mukherjee C,et al.Virtual ligand screening of the p300/CBP histone acetyltransferase:identification of a selective small molecule inhibitor[J].Chem Biol,2010,17(5):471-482.
[47]Shrimp J H,Sorum A W,Garlick J M,et al.Characterizing the covalent targets of a small molecule inhibitor of the lysine acetyltransferase P300[J].ACS Med Chem Lett,2016,7(2):151-155.
[48]Lasko L M,Jakob C G,Edalji R P,et al.Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours[J].Nature,2017,550(7674):128-132.
[49]Michaelides M R,Kluge A,Patane M,et al.Discovery of spiro oxazolidinediones as selective,orally bioavailable inhibitors of p300/CBPhistone acetyltransferases[J].ACS Med Chem Lett,2018,9(1):28-33.