Procaspase-3小分子激活剂的研究进展
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摘要
Caspase-3作为细胞凋亡通路的下游关键执行蛋白,在细胞凋亡信号传导中扮演着重要的角色。开发直接通过激活高表达状态的procaspase-3成为caspase-3,进而重启肿瘤细胞凋亡的小分子药物,已成为克服中/上游凋亡蛋白突变的有效策略。目前,以procaspase-3为靶点已经报道了一些特异性小分子激活剂,至今还没有上市药物,开发直接激活procaspase-3的新型药物仍然是一项重要和艰难的挑战。本文介绍了procaspase-3与肿瘤之间的关系及小分子procaspase-3激活剂的研究进展。
Caspase-3 plays a very important role in the apoptotic cascade as the downstream key executioner caspase. Identification of small molecules that restart the apoptosis of tumor cells by directly activating over-expression procaspase-3 to active caspase-3 has become an effective strategy for overcoming the mutation of the middle/upstream apoptotic protein. Currently, some procaspase-3 small molecule activators have been reported, but no marketed drugs are available so far. The development of procaspase-3 activator remains an important and difficult challenge. In this article, the relationship between procaspase-3 and tumor and the research progress of procaspase-3 small molecule activators were introduced.
Caspase-3 plays a very important role in the apoptotic cascade as the downstream key executioner caspase. Identification of small molecules that restart the apoptosis of tumor cells by directly activating over-expression procaspase-3 to active caspase-3 has become an effective strategy for overcoming the mutation of the middle/upstream apoptotic protein. Currently, some procaspase-3 small molecule activators have been reported, but no marketed drugs are available so far. The development of procaspase-3 activator remains an important and difficult challenge. In this article, the relationship between procaspase-3 and tumor and the research progress of procaspase-3 small molecule activators were introduced.
引文
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[24]WOLAN D W,ZORN J A,GRAY D C,et al.Small-molecule activators of a proenzyme[J].Science,2009,326(5954):853-858.
[25]BOTHAM R C,FAN T M,IM I,et al.Dual small-molecule targeting of procaspase-3 dramatically enhances zymogen activation and anticancer activity[J].J Am Chem Soc,2014,136(4):1312-1319.
[26]SCHIPPER J L,MACKENZIE S H,SHARMA A,et al.Abifunctional allosteric site in the dimer interface of procaspase-3[J].Biophys Chem,2011,159(1):100-109.
[27]MATSUO T,YAMADA K,ISHIDA M,et al.Effect of a procaspase-activating compound on the catalytic activity of mature caspase-3[J].Bullet Chem Soc Japan,2015,88(9):1221-1229.
[2]李敏,林俊.细胞凋亡途径及其机制[J].国际妇产科学杂志,2014(2):103-107.
[3]REN L P,LI X J,JING S J.Influence of sophoridine on proliferation and caspase-3/bcl-2/bax signaling pathway of human pancreatic cancer cell line capan-1 cells[J].Chin JMod Appl Pharm(中国现代应用药学),2017,34(3):325-328.
[4]IZBAN K F,WRONE SMITH T,HSI ED,et al.Characterization of the interleukin-1β-converting enzyme/ced-3-family protease,caspase-3/cpp32,in hodgkin’s disease:lack of caspase-3 expression in nodular lymphocyte predominance hodgkin’s disease[J].Am J Pathol,1999,154(5):1439-1447.
[5]SVINGEN P A,LOEGERING D,RODRIQUEZ J,et al.Components of the cell death machine and drug sensitivity of the national cancer institute cell line panel[J].Clin Cancer Res,2004,10(20):6807-6820.
[6]FINK D,SCHLAGBAUER WADL H,SELZER E,et al.Elevated procaspase levels in human melanoma[J].Melanoma Res,2001,11(4):385-393.
[7]NAKAGAWARA A,NAKAMURA Y,IKEDA H,et al.High levels of expression and nuclear localization of interleukin-1βconverting enzyme(ICE)and CPP32 in favorable human neuroblastomas[J].Cancer Res,1997,57(20):4578-4584.
[8]PERSAD R,LIU C,WU T T,et al.Overexpression of caspase-3 in hepatocellular carcinomas[J].Mod Pathol,2004,17(7):861-867.
[9]KREPELA E,PROCHáZKA J,LIU X Y,et al.Increased expression of Apaf-1 and procaspase-3 and the functionality of intrinsic apoptosis apparatus in non-small cell lung carcinoma[J].Biol Chem,2004,385(2):153-168.
[10]O’DONOVAN N,CROWN J,STUNELL H,et al.Caspase 3in breast cancer[J].Clin Cancer Res,2003,9(2):738-742.
[11]PUTT K S,CHEN G W,J M PEARSON,et al.Small-molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy[J].Nat Chem Biol,2006,2(10):543-550.
[12]PETERSON Q P,HSU D C,GOODE D R,et al.Procaspase-3activation as an anti-cancer strategy:structure-activity relationship of procaspase-activating compound 1(PAC-1)and Its cellular co-localization with caspase-3[J].J Med Chem,2009,52(18):5721-5731.
[13]ROTH H S,HERGENROTHER P J.Derivatives of procaspase-activating compound 1(PAC-1)and their anticancer activities[J].Curr Med Chem,2016,23(3):201-241.
[14]PETERSON Q P,HSU D C,NOVOTNY C J,et al.Discovery and canine preclinical assessment of a nontoxic procaspase-3-activating compound[J].Cancer Res,2010,70(18):7232-7241.
[15]JI S,LI M Z,WEN Z,et al.Development and validation of a simple HPLC assay for the quantitation of SM-1,a novel derivative of the PAC-1 anticancer agent,and an initial pharmacokinetics study in rats[J].Anal Meth,2015,7(22):9562-9567.
[16]ZAMAN S,WANG R,GANDHI V.Targeting executioner procaspase-3 with the procaspase-activating compound B-PAC-1 induces apoptosis in multiple myeloma cells[J].Exp Hematol,2015,43(11):951-962.
[17]SARKAR A,BALAKRITHNAN K,CHEN J,et al.Molecular evidence of Zn chelation of the procaspase activating compound B-PAC-1 in B cell lymphoma[J].Oncotarget,2016,7(3):3461-3476.
[18]WANG F Y,WANG L H,ZHAO Y F,et al.A novel small-molecule activator of procaspase-3 induces apoptosis in cancer cells and reduces tumor growth in human breast,liver and gallbladder cancer xenografts[J].Mol Oncol,2014,8(8):1640-1652.
[19]WANG F,LIU Y,WANG L,et al.Targeting procaspase-3with WF-208,a novel PAC-1 derivative,causes selective cancer cell apoptosis[J].J Cell Mol Med,2015,19(8):1916-1928.
[20]?STRAND O A H,AZIZ G,ALI S F,et al.Synthesis and initial in vitro biological evaluation of two new zinc-chelating compounds:comparison with TPEN and PAC-1[J].Bioorg Med Chem,2013,21(17):5175-5181.
[21]ROTH H S,BOTHAM R C,SCHMID S C,et al.Removal of metabolic liabilities enables development of derivatives of procaspase-activating compound 1(pac-1)with improved pharmacokinetics[J].J Med Chem,2015,58(9):4046-4065.
[22]MA J,CHEN D,LU K,et al.Design,synthesis,and structure-activity relationships of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety as potent antitumor agents[J].Eur J Med Chem,2014,86:257-269.
[23]MA J,ZHANG G,HAN X,et al.Synthesis and biological evaluation of benzothiazole derivatives bearing the ortho-Hydroxy-N-acylhydrazone moiety as potent antitumor agents[J].Archiv der Pharmazie,2014,347(12):936-949.
[24]WOLAN D W,ZORN J A,GRAY D C,et al.Small-molecule activators of a proenzyme[J].Science,2009,326(5954):853-858.
[25]BOTHAM R C,FAN T M,IM I,et al.Dual small-molecule targeting of procaspase-3 dramatically enhances zymogen activation and anticancer activity[J].J Am Chem Soc,2014,136(4):1312-1319.
[26]SCHIPPER J L,MACKENZIE S H,SHARMA A,et al.Abifunctional allosteric site in the dimer interface of procaspase-3[J].Biophys Chem,2011,159(1):100-109.
[27]MATSUO T,YAMADA K,ISHIDA M,et al.Effect of a procaspase-activating compound on the catalytic activity of mature caspase-3[J].Bullet Chem Soc Japan,2015,88(9):1221-1229.