Src及其信号通路在肿瘤发生过程中的作用
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摘要
非受体酪氨酸激酶(NRTKs)能够将来源于细胞外受体接受的信号传递给细胞质内的其他蛋白或者是传递到细胞核,从而调节细胞的多种生理功能。其中,Src家族蛋白酪氨酸激酶(SFKs)作为一类重要的非受体酪氨酸激酶,在细胞的生长,分化,转移和生存中都有着重要的作用。其中,在肿瘤细胞的转移过程中,Src可以与整合素(Integrin)家族的不同亚型作用,介导不同的信号通路,从而影响细胞的运动性和转移性。在这篇综述中,将会对Src及其在肿瘤中的作用和靶向Src激酶的一些药物做一个简单的介绍。
Non-Receptor Tyrosine Kinases(NRTKs) could transmit the signaling to the cytoplasmic proteins or to the nucleus,which are obtained from extracellular receptors, to regulate several physiological cellular processes. Src-family protein kinases(SFKs),as a series of important NRTKs, play an important role in cell growth, division, migration and survival signaling pathways. During the process of migration, Src could interact with different subtypes of Integrin to induce various pathways involved in cell mobility and migration. In this review, I would give a brief introduction of Src and its signaling in cancer, together with some Src kinase inhibitors.
Non-Receptor Tyrosine Kinases(NRTKs) could transmit the signaling to the cytoplasmic proteins or to the nucleus,which are obtained from extracellular receptors, to regulate several physiological cellular processes. Src-family protein kinases(SFKs),as a series of important NRTKs, play an important role in cell growth, division, migration and survival signaling pathways. During the process of migration, Src could interact with different subtypes of Integrin to induce various pathways involved in cell mobility and migration. In this review, I would give a brief introduction of Src and its signaling in cancer, together with some Src kinase inhibitors.
引文
[1]Hubbard SR,Till JH.Protein tyrosine kinase structure and function[J].Annu Rev Biochem,2000,69:373-398.
[2]Scheijen B,Griffin JD.Tyrosine kinase oncogenes in normal hematopoiesis and hematological disease[J].Oncogene,2002,21:3314-3333.
[3]Chase A,Cross NC.Signal transduction therapy in haematological malignancies:identification and targeting of tyrosine kinases[J].Clin Sci(Lond),2006,111:233-249.
[4]Paul MK,Mukhopadhyay AK:Tyrosine kinase-Role and significance in Cancer[J].Int J Med Sci,2004,1:101-115.
[5]Kosior K,Lewandowska-Grygiel M,Giannopoulos K.Tyrosine kinase inhibitors in hematological malignancies[J].Postepy Hig Med Dosw(Online),2011,65:819-828.
[6]Wadleigh M,DeAngelo DJ,Griffin JD,et al.After chronic myelogenous leukemia:tyrosine kinase inhibitors in other hematologic malignancies[J].Blood,2005,105:22-30.
[7]Rossi JF.Targeted Therapies in Adult B-Cell Malignancies[J].Biomed Res Int,2015,2015:217593.
[8]Al-Obeidi FA,Lam KS:Development of inhibitors for protein tyrosine kinases[J].Oncogene,2000,19:5690-5701.
[9]Lahiry P,Torkamani A,Schork NJ,et al.Kinase mutations in human disease:interpreting genotype-phenotype relationships[J].Nat Rev Genet,2010,11:60-74.
[10]Heinrich PC,Behrmann I,Haan S,Hermanns HM,Muller-Newen G,Schaper F:Principles of interleukin(IL)-6-type cytokine signalling and its regulation[J].Biochem J,2003,374:1-20.
[11]Welch PJ,Wang JY.A C-terminal protein-binding domain in the retinoblastoma protein regulates nuclear c-Abl tyrosine kinase in the cell cycle[J].Cell,1993,75:779-790.
[12]Prieto-Echague V,Miller WT.Regulation of ack-family nonreceptor tyrosine kinases[J].J Signal Transduct,2011,2011:742372.
[13]Arora A,Scholar EM.Role of tyrosine kinase inhibitors in cancer therapy[J].J Pharmacol Exp Ther,2005,315:971-979.
[14]Thomas SM,Birtwistle N,Brady M,Burke JF:Public-sector patents on human DNA[J].Nature,1997,388:709.
[15]Parsons SJ,Parsons JT.Src family kinases,key regulators of signal transduction[J].Oncogene,2004,23:7906-7909.
[16]Boggon TJ,Eck MJ.Structure and regulation of Src family kinases[J].Oncogene 2004,23:7918-7927.
[17]Bibbins KB,Boeuf H,Varmus HE.Binding of the Src SH2 domain to phosphopeptides is determined by residues in both the SH2 domain and the phosphopeptides[J].Mol Cell Biol,1993,13:7278-7287.
[18]Roussel RR,Brodeur SR,Shalloway D,et al.Selective binding of activated pp60c-src by an immobilized synthetic phosphopeptide modeled on the carboxyl terminus of pp60c-src[J].Proc Natl Acad Sci U S A,1991,88:10696-10700.
[19]Bromann PA,Korkaya H,Courtneidge SA:The interplay between Src family kinases and receptor tyrosine kinases[J].Oncogene,2004,23:7957-7968.
[20]Luttrell DK,Luttrell LM:Not so strange bedfellows:G-protein-coupled receptors and Src family kinases[J].Oncogene,2004,23:7969-7978.
[21]Summy JM,Gallick GE:Src family kinases in tumor progression and metastasis[J].Cancer Metastasis Rev,2003,22:337-358.
[22]Xu W,Harrison SC,Eck MJ:Three-dimensional structure of the tyrosine kinase c-Src[J].Nature,1997,385:595-602.
[23]Silva CM:Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis[J].Oncogene,2004,23:8017-8023.
[24]Harris KF,Shoji I,Cooper EM,et al.Ubiquitin-mediated degradation of active Src tyrosine kinase[J].Proc Natl Acad Sci U S A,1999,96:13738-13743.
[25]Shimakage M,Kawahara K,Kikkawa N,et al.Down-regulation of drs mRNAin human colon adenocarcinomas[J].Int J Cancer,2000,87:5-11.
[26]Hakak Y,Martin GS:Ubiquitin-dependent degradation of active Src[J].Curr Biol,1999,9:1039-1042.
[27]Mao W,Irby R,Coppola D,Fu L,et al.Activation of c-Src by receptor tyrosine kinases in human colon cancer cells with high metastatic potential[J].Oncogene,1997,15:3083-3090.
[28]Irby RB,Mao W,Coppola D,et al.Activating SRC mutation in a subset of advanced human colon cancers[J].Nat Genet,1999,21:187-190.
[29]Irby R,Mao W,Coppola D,et al.Overexpression of normal c-Src in poorly metastatic human colon cancer cells enhances primary tumor growth but not metastatic potential[J].Cell Growth Differ,1997,8:1287-1295.
[30]Staley CA,Parikh NU,Gallick GE.Decreased tumorigenicity of a human colon adenocarcinoma cell line by an antisense expression vector specific for c-Src[J].Cell Growth Differ,1997,8:269-274.
[31]Matsumoto T,Jiang J,Kiguchi K,et al.Targeted expression of c-Src in epidermal basal cells leads to enhanced skin tumor promotion,malignant progression,and metastasis[J].Cancer Res,2003,63:4819-4828.
[32]Jones RJ,Avizienyte E,Wyke AW,et al.Elevated c-Src is linked to altered cell-matrix adhesion rather than proliferation in KM12C human colorectal cancer cells[J].Br J Cancer,2002,87:1128-1135.
[33]Okada M.Regulation of the SRC family kinases by Csk[J].Int J Biol Sci,2012,8:1385-1397.
[34]Ku M,Wall M,MacKinnon RN,et al.Src family kinases and their role in hematological malignancies[J].Leuk Lymphoma,2015,56:577-586.
[35]Warmuth M,Damoiseaux R,Liu Y,et al.SRC family kinases:potential targets for the treatment of human cancer and leukemia[J].Curr Pharm Des,2003,9:2043-2059.
[36]Malek RL,Irby RB,Guo QM,et al.Identification of Src transformation fingerprint in human colon cancer[J].Oncogene,2002,21:7256-7265.
[37]Kato JY,Takeya T,Grandori C,et al.Amino acid substitutions sufficient to convert the nontransforming p60c-src protein to a transforming protein[J].Mol Cell Biol,1986,6:4155-4160.
[38]Levy JB,Iba H,Hanafusa H:Activation of the transforming potential of p60c-src by a single amino acid change[J].Proc Natl Acad Sci U S A,1986,83:4228-4232.
[39]Thomas SM,Brugge JS:Cellular functions regulated by Src family kinases[J].Annu Rev Cell Dev Biol,1997,13:513-609.
[40]Giancotti FG,Tarone G:Positional control of cell fate through joint integrin/receptor protein kinase signaling[J].Annu Rev Cell Dev Biol,2003,19:173-206.
[41]Nader GP,Ezratty EJ,Gundersen GG:FAK,talin and PIPKIgamma regulate endocytosed integrin activation to polarize focal adhesion assembly[J].Nat Cell Biol,2016,18:491-503.
[42]Kaplan KB,Bibbins KB,Swedlow JR,Arnaud M,Morgan DO,Varmus HE:Association of the amino-terminal half of c-Src with focal adhesions alters their properties and is regulated by phosphorylation of tyrosine 527[J].EMBO J,1994,13:4745-4756.
[43]Schaller MD,Hildebrand JD,Parsons JT:Complex formation with focal adhesion kinase:A mechanism to regulate activity and subcellular localization of Src kinases[J].Mol Biol Cell,1999,10:3489-3505.
[44]Timpson P,Jones GE,Frame MC,Brunton VG:Coordination of cell polarization and migration by the Rho family GTPases requires Src tyrosine kinase activity.Curr Biol,2001,11:1836-1846.
[45]Kanner SB,Reynolds AB,Vines RR,Parsons JT:Monoclonal antibodies to individual tyrosine-phosphorylated protein substrates of oncogene-encoded tyrosine kinases[J].Proc Natl Acad Sci U S A,1990,87:3328-3332.
[46]Obergfell A,Eto K,Mocsai A,Buensuceso C,Moores SL,Brugge JS,Lowell CA,Shattil SJ:Coordinate interactions of Csk,Src,and Syk kinases with[alpha]IIb[beta]3 initiate integrin signaling to the cytoskeleton[J].J Cell Biol,2002,157:265-275.
[47]Mitra SK,Schlaepfer DD:Integrin-regulated FAK-Src signaling in normal and cancer cells[J].Curr Opin Cell Biol,2006,18:516-523.
[48]Chodniewicz D,Klemke RL:Regulation of integrin-mediated cellular responses through assembly of a CAS/Crk scaffold[J].Biochim Biophys Acta,2004,1692:63-76.
[49]ten Klooster JP,Jaffer ZM,Chernoff J,Hordijk PL:Targeting and activation of Rac1 are mediated by the exchange factor beta-Pix[J].J Cell Biol,2006,172:759-769.
[50]Arias-Salgado EG,Lizano S,Shattil SJ,Ginsberg MH:Specification of the direction of adhesive signaling by the integrin beta cytoplasmic domain[J].JBiol Chem,2005,280:29699-29707.
[51]Arias-Salgado EG,Lizano S,Sarkar S,et al.Src kinase activation by direct interaction with the integrin beta cytoplasmic domain[J].Proc Natl Acad Sci U S A,2003,100:13298-13302.
[52]Huveneers S,van den Bout I,Sonneveld P,et al.Integrin alpha v beta3 controls activity and oncogenic potential of primed c-Src[J].Cancer Res,2007,67:2693-2700.
[53]Woodside DG,Obergfell A,Leng L,et al.Activation of Syk protein tyrosine kinase through interaction with integrin beta cytoplasmic domains[J].Curr Biol,2001,11:1799-1804.
[54]Marignani PA,Carpenter CL:Vav2 is required for cell spreading[J].J Cell Biol,2001,154:177-186.
[55]Boschelli DH,Wang YD,Johnson S,et al.7-Alkoxy-4-phenylamino-3-quinolinecar-bonitriles as dual inhibitors of Src and Abl kinases[J].J Med Chem,2004,47:1599-1601.
[56]Lombardo LJ,Lee FY,Chen P,et al.Discovery of N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide(BMS-354825),a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays[J].J Med Chem2004;47:6658-6661.
[57]Huang WS,Metcalf CA,Sundaramoorthi R,et al.Discovery of3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-y l)methyl]-3-(trifluoromethyl)phenyl}benzamide(AP24534),a potent,orally active pan-inhibitor of breakpoint cluster regionabelson(BCR-ABL)kinase including the T315I gatekeeper mutant[J].J Med Chem,2010,53:4701-4719.
[58]Hennequin LF,Stokes ES,Thomas AP,et al.Novel 4-anilinoquinazolines with C-7 basic side chains:design and structure activity relationship of a series of potent,orally active,VEGF receptor tyrosine kinase inhibitors[J].JMed Chem,2002,45:1300-1312.
[59]Nowak D,Boehrer S,Hochmuth S,et al.Src kinase inhibitors induce apoptosis and mediate cell cycle arrest in lymphoma cells[J].Anticancer Drugs,2007,18:981-995.
[2]Scheijen B,Griffin JD.Tyrosine kinase oncogenes in normal hematopoiesis and hematological disease[J].Oncogene,2002,21:3314-3333.
[3]Chase A,Cross NC.Signal transduction therapy in haematological malignancies:identification and targeting of tyrosine kinases[J].Clin Sci(Lond),2006,111:233-249.
[4]Paul MK,Mukhopadhyay AK:Tyrosine kinase-Role and significance in Cancer[J].Int J Med Sci,2004,1:101-115.
[5]Kosior K,Lewandowska-Grygiel M,Giannopoulos K.Tyrosine kinase inhibitors in hematological malignancies[J].Postepy Hig Med Dosw(Online),2011,65:819-828.
[6]Wadleigh M,DeAngelo DJ,Griffin JD,et al.After chronic myelogenous leukemia:tyrosine kinase inhibitors in other hematologic malignancies[J].Blood,2005,105:22-30.
[7]Rossi JF.Targeted Therapies in Adult B-Cell Malignancies[J].Biomed Res Int,2015,2015:217593.
[8]Al-Obeidi FA,Lam KS:Development of inhibitors for protein tyrosine kinases[J].Oncogene,2000,19:5690-5701.
[9]Lahiry P,Torkamani A,Schork NJ,et al.Kinase mutations in human disease:interpreting genotype-phenotype relationships[J].Nat Rev Genet,2010,11:60-74.
[10]Heinrich PC,Behrmann I,Haan S,Hermanns HM,Muller-Newen G,Schaper F:Principles of interleukin(IL)-6-type cytokine signalling and its regulation[J].Biochem J,2003,374:1-20.
[11]Welch PJ,Wang JY.A C-terminal protein-binding domain in the retinoblastoma protein regulates nuclear c-Abl tyrosine kinase in the cell cycle[J].Cell,1993,75:779-790.
[12]Prieto-Echague V,Miller WT.Regulation of ack-family nonreceptor tyrosine kinases[J].J Signal Transduct,2011,2011:742372.
[13]Arora A,Scholar EM.Role of tyrosine kinase inhibitors in cancer therapy[J].J Pharmacol Exp Ther,2005,315:971-979.
[14]Thomas SM,Birtwistle N,Brady M,Burke JF:Public-sector patents on human DNA[J].Nature,1997,388:709.
[15]Parsons SJ,Parsons JT.Src family kinases,key regulators of signal transduction[J].Oncogene,2004,23:7906-7909.
[16]Boggon TJ,Eck MJ.Structure and regulation of Src family kinases[J].Oncogene 2004,23:7918-7927.
[17]Bibbins KB,Boeuf H,Varmus HE.Binding of the Src SH2 domain to phosphopeptides is determined by residues in both the SH2 domain and the phosphopeptides[J].Mol Cell Biol,1993,13:7278-7287.
[18]Roussel RR,Brodeur SR,Shalloway D,et al.Selective binding of activated pp60c-src by an immobilized synthetic phosphopeptide modeled on the carboxyl terminus of pp60c-src[J].Proc Natl Acad Sci U S A,1991,88:10696-10700.
[19]Bromann PA,Korkaya H,Courtneidge SA:The interplay between Src family kinases and receptor tyrosine kinases[J].Oncogene,2004,23:7957-7968.
[20]Luttrell DK,Luttrell LM:Not so strange bedfellows:G-protein-coupled receptors and Src family kinases[J].Oncogene,2004,23:7969-7978.
[21]Summy JM,Gallick GE:Src family kinases in tumor progression and metastasis[J].Cancer Metastasis Rev,2003,22:337-358.
[22]Xu W,Harrison SC,Eck MJ:Three-dimensional structure of the tyrosine kinase c-Src[J].Nature,1997,385:595-602.
[23]Silva CM:Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis[J].Oncogene,2004,23:8017-8023.
[24]Harris KF,Shoji I,Cooper EM,et al.Ubiquitin-mediated degradation of active Src tyrosine kinase[J].Proc Natl Acad Sci U S A,1999,96:13738-13743.
[25]Shimakage M,Kawahara K,Kikkawa N,et al.Down-regulation of drs mRNAin human colon adenocarcinomas[J].Int J Cancer,2000,87:5-11.
[26]Hakak Y,Martin GS:Ubiquitin-dependent degradation of active Src[J].Curr Biol,1999,9:1039-1042.
[27]Mao W,Irby R,Coppola D,Fu L,et al.Activation of c-Src by receptor tyrosine kinases in human colon cancer cells with high metastatic potential[J].Oncogene,1997,15:3083-3090.
[28]Irby RB,Mao W,Coppola D,et al.Activating SRC mutation in a subset of advanced human colon cancers[J].Nat Genet,1999,21:187-190.
[29]Irby R,Mao W,Coppola D,et al.Overexpression of normal c-Src in poorly metastatic human colon cancer cells enhances primary tumor growth but not metastatic potential[J].Cell Growth Differ,1997,8:1287-1295.
[30]Staley CA,Parikh NU,Gallick GE.Decreased tumorigenicity of a human colon adenocarcinoma cell line by an antisense expression vector specific for c-Src[J].Cell Growth Differ,1997,8:269-274.
[31]Matsumoto T,Jiang J,Kiguchi K,et al.Targeted expression of c-Src in epidermal basal cells leads to enhanced skin tumor promotion,malignant progression,and metastasis[J].Cancer Res,2003,63:4819-4828.
[32]Jones RJ,Avizienyte E,Wyke AW,et al.Elevated c-Src is linked to altered cell-matrix adhesion rather than proliferation in KM12C human colorectal cancer cells[J].Br J Cancer,2002,87:1128-1135.
[33]Okada M.Regulation of the SRC family kinases by Csk[J].Int J Biol Sci,2012,8:1385-1397.
[34]Ku M,Wall M,MacKinnon RN,et al.Src family kinases and their role in hematological malignancies[J].Leuk Lymphoma,2015,56:577-586.
[35]Warmuth M,Damoiseaux R,Liu Y,et al.SRC family kinases:potential targets for the treatment of human cancer and leukemia[J].Curr Pharm Des,2003,9:2043-2059.
[36]Malek RL,Irby RB,Guo QM,et al.Identification of Src transformation fingerprint in human colon cancer[J].Oncogene,2002,21:7256-7265.
[37]Kato JY,Takeya T,Grandori C,et al.Amino acid substitutions sufficient to convert the nontransforming p60c-src protein to a transforming protein[J].Mol Cell Biol,1986,6:4155-4160.
[38]Levy JB,Iba H,Hanafusa H:Activation of the transforming potential of p60c-src by a single amino acid change[J].Proc Natl Acad Sci U S A,1986,83:4228-4232.
[39]Thomas SM,Brugge JS:Cellular functions regulated by Src family kinases[J].Annu Rev Cell Dev Biol,1997,13:513-609.
[40]Giancotti FG,Tarone G:Positional control of cell fate through joint integrin/receptor protein kinase signaling[J].Annu Rev Cell Dev Biol,2003,19:173-206.
[41]Nader GP,Ezratty EJ,Gundersen GG:FAK,talin and PIPKIgamma regulate endocytosed integrin activation to polarize focal adhesion assembly[J].Nat Cell Biol,2016,18:491-503.
[42]Kaplan KB,Bibbins KB,Swedlow JR,Arnaud M,Morgan DO,Varmus HE:Association of the amino-terminal half of c-Src with focal adhesions alters their properties and is regulated by phosphorylation of tyrosine 527[J].EMBO J,1994,13:4745-4756.
[43]Schaller MD,Hildebrand JD,Parsons JT:Complex formation with focal adhesion kinase:A mechanism to regulate activity and subcellular localization of Src kinases[J].Mol Biol Cell,1999,10:3489-3505.
[44]Timpson P,Jones GE,Frame MC,Brunton VG:Coordination of cell polarization and migration by the Rho family GTPases requires Src tyrosine kinase activity.Curr Biol,2001,11:1836-1846.
[45]Kanner SB,Reynolds AB,Vines RR,Parsons JT:Monoclonal antibodies to individual tyrosine-phosphorylated protein substrates of oncogene-encoded tyrosine kinases[J].Proc Natl Acad Sci U S A,1990,87:3328-3332.
[46]Obergfell A,Eto K,Mocsai A,Buensuceso C,Moores SL,Brugge JS,Lowell CA,Shattil SJ:Coordinate interactions of Csk,Src,and Syk kinases with[alpha]IIb[beta]3 initiate integrin signaling to the cytoskeleton[J].J Cell Biol,2002,157:265-275.
[47]Mitra SK,Schlaepfer DD:Integrin-regulated FAK-Src signaling in normal and cancer cells[J].Curr Opin Cell Biol,2006,18:516-523.
[48]Chodniewicz D,Klemke RL:Regulation of integrin-mediated cellular responses through assembly of a CAS/Crk scaffold[J].Biochim Biophys Acta,2004,1692:63-76.
[49]ten Klooster JP,Jaffer ZM,Chernoff J,Hordijk PL:Targeting and activation of Rac1 are mediated by the exchange factor beta-Pix[J].J Cell Biol,2006,172:759-769.
[50]Arias-Salgado EG,Lizano S,Shattil SJ,Ginsberg MH:Specification of the direction of adhesive signaling by the integrin beta cytoplasmic domain[J].JBiol Chem,2005,280:29699-29707.
[51]Arias-Salgado EG,Lizano S,Sarkar S,et al.Src kinase activation by direct interaction with the integrin beta cytoplasmic domain[J].Proc Natl Acad Sci U S A,2003,100:13298-13302.
[52]Huveneers S,van den Bout I,Sonneveld P,et al.Integrin alpha v beta3 controls activity and oncogenic potential of primed c-Src[J].Cancer Res,2007,67:2693-2700.
[53]Woodside DG,Obergfell A,Leng L,et al.Activation of Syk protein tyrosine kinase through interaction with integrin beta cytoplasmic domains[J].Curr Biol,2001,11:1799-1804.
[54]Marignani PA,Carpenter CL:Vav2 is required for cell spreading[J].J Cell Biol,2001,154:177-186.
[55]Boschelli DH,Wang YD,Johnson S,et al.7-Alkoxy-4-phenylamino-3-quinolinecar-bonitriles as dual inhibitors of Src and Abl kinases[J].J Med Chem,2004,47:1599-1601.
[56]Lombardo LJ,Lee FY,Chen P,et al.Discovery of N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide(BMS-354825),a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays[J].J Med Chem2004;47:6658-6661.
[57]Huang WS,Metcalf CA,Sundaramoorthi R,et al.Discovery of3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-y l)methyl]-3-(trifluoromethyl)phenyl}benzamide(AP24534),a potent,orally active pan-inhibitor of breakpoint cluster regionabelson(BCR-ABL)kinase including the T315I gatekeeper mutant[J].J Med Chem,2010,53:4701-4719.
[58]Hennequin LF,Stokes ES,Thomas AP,et al.Novel 4-anilinoquinazolines with C-7 basic side chains:design and structure activity relationship of a series of potent,orally active,VEGF receptor tyrosine kinase inhibitors[J].JMed Chem,2002,45:1300-1312.
[59]Nowak D,Boehrer S,Hochmuth S,et al.Src kinase inhibitors induce apoptosis and mediate cell cycle arrest in lymphoma cells[J].Anticancer Drugs,2007,18:981-995.