凋亡抑制蛋白抑制剂临床研究进展
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摘要
凋亡抑制蛋白(IAPs)是调控细胞凋亡的关键蛋白,且在多种肿瘤细胞中过表达。人类肿瘤基因组学研究表明,抑制凋亡抑制蛋白的表达,可有效抑制肿瘤的生长和转移,IAPs抑制剂已成为当前抗肿瘤新药研发的热点之一。现总结IAPs抑制剂的研究进展,为其在药学领域进一步研究与应用提供参考。
Inhibitors of apoptosis proteins(IAPs) are key proteins in controlling apoptosis and are overexpressed in many cancer cells.The research about human cancer genomics shows that inhibition of IAPs expressed can effectively suppress tumor growth and metastasis. IAPs antagonists have become one of the hotspots in new anti-tumor drugs' research and development. This paper summarizes research progress of IAPs antagonists to provide references for its further research and application in the field of pharmacy.
Inhibitors of apoptosis proteins(IAPs) are key proteins in controlling apoptosis and are overexpressed in many cancer cells.The research about human cancer genomics shows that inhibition of IAPs expressed can effectively suppress tumor growth and metastasis. IAPs antagonists have become one of the hotspots in new anti-tumor drugs' research and development. This paper summarizes research progress of IAPs antagonists to provide references for its further research and application in the field of pharmacy.
引文
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[2]Salvesen GS,Duckett CS.IAP proteins:blocking the road to death's door[J].Nat Rev Mol Cell Biol,2002,3(6):401-410.
[3]Hunter AM,La Casse EC,Korneluk RG.The inhibitors of apoptosis(IAPs)as cancer targets[J].Apoptosis,2007,12(9):1543-1568.
[4]Crook NE,Clem RJ,Miller LK.An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif[J].J Virol,1993,67(4):2168-2174.
[5]LaCasse EC,Beug ST,Korneluk RG.The inhibitors of apoptosis(IAPs):Over 20 years of research into life and death[J].Semin Cell Dev Biol,2015,39:70-71.
[6]Gyrd-Hansen M,Meier P.IAPs:from caspase inhibitors to modulators of NF-kappaB,inflammation and cancer[J].Nat Rev Cancer,2010,10(8):561-574.
[7]Samuel T,Welsh K,Lober T,et al.Distinct BIR domains of cIAP1mediate binding to and ubiquitination of tumor necrosis factor receptor-associated factor 2 and second mitochondrial activator of caspases[J].J Biol Chem,2006,281(2):1080-1090.
[8]Varfolomeev E,Blankenship JW,Wayson SM,et al.IAPantagonists induce autoubiquitination of c-IAPs,NF-kappaBactivation,and TNFalpha-dependent apoptosis[J].Cell,2007,131(4):669-681.
[9]Vince JE,Wong WW,Khan N,et al.IAP antagonists target cIAP1to induce TNFalpha-dependent apoptosis[J].Cell,2007,131(4):682-693.
[10]Bai L,Smith DC,Wang S.Small-molecule SMAC mimetics as new cancer therapeutics[J].Pharmacol Ther,2014,144(1):82-95.
[11]Qiu W,Liu H,Sebastini A,et al.An apoptosis-independent role of SMAC in tumor suppression[J].Oncogene,2013,32(19):2380-2389.
[12]Hashimoto K,Saito B,Miyamoto N,et al.Design and synthesis of potent inhibitor of apoptosis(IAP)proteins antagonists bearing an octahydropyrrolo[1,2-a]pyrazine scaffold as a novel proline mimetic[J].J Med Chem,2013,56(3):1228-1246.
[13]Sumi H,Yabuki M,Iwai K,et al.Antitumor activity and pharmacodynamic biomarkers of a novel and orally available smallmolecule antagonist of inhibitor of apoptosis proteins[J].Mol Cancer Ther,2013,12(2):230-240.
[14]Zobel K,Wang L,Varfolomeev E,et al.Design,synthesis,and biological activity of a potent Smac mimetic that sensitizes cancer cells to apoptosis by antagonizing IAPs[J].ACS Chem Biol,2006,1(8):525-533.
[15]Cossu F,Malvezzi F,Canevari G,et al.Recognition of Smac-mimetic compounds by the BIR domain of cIAP1[J].Protein Sci,2010,19(12):2418-2429.
[16]Silke J,Meier P.Inhibitor of apoptosis(IAP)proteinsmodulators of cell death and inflammation[J].Cold Spring Harb Perspect Biol,2013,5(2):a008730.
[17]Weisberg E,Ray A,Barrett R,et al.Smac mimetics:implications for enhancement of targeted therapies in leukemia[J].Leukemia,2010,24(12):2100-2109.
[18]Chen KF,Lin JP,Shiau CW,et al.Inhibition of Bcl-2 improves effect of LCL161,a SMAC mimetic,in hepatocellular carcinoma cells[J].Biochem Pharmacol,2012,84(3):268-277.
[19]Bardia A,Parton M,Kümmel S,et al.Paclitaxel With Inhibitor of Apoptosis Antagonist,LCL161,for Localized Triple-Negative Breast Cancer,Prospectively Stratified by Gene Signature in a Biomarker-Driven Neoadjuvant Trial[J].J Clin Oncol,2018:JCO2017748392.
[20]La Casse EC,Mahoney DJ,Cheung HH,et al.IAP-targeted therapies for cancer[J].Oncogene,2008,27(48):6252-6275.
[21]Ward GA,Lewis EJ,Ahn JS,et al.ASTX660,a Novel Non-peptidomimetic Antagonist of cIAP1/2 and XIAP,Potently Induces TNFα-Dependent Apoptosis in Cancer Cell Lines and Inhibits Tumor Growth[J].Mol Cancer Ther,2018,17(7):1381-1391.
[22]Johnson CN,Ahn JS,Buck IM,et al.A Fragment-Derived Clinical Candidate for Antagonism of X-Linked and Cellular Inhibitor of Apoptosis Proteins:1-(6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl)-2-[(2 R,5R)-5-methyl-2-([(3R)-3-methylmorpholin-4-yl]methyl)piperazin-1-yl]ethan-1-one(ASTX660)[J].J Med Chem,2018,61(16):7314-7329.
[23]Hurwitz HI,Smith DC,Pitot HC,et al.Safety,pharmacokinetics,and pharmacodynamic properties of oral DEBIO1143(AT-406)in patients with advanced cancer:results of a first-in-man study[J].Cancer Chemother Pharmacol,2015,75(4):851-859.
[24]Thibault B,Genre L,Le Naour A,etal.DEBIO 1143,an IAPinhibitor,reverses carboplatin resistance in ovarian cancer cells and triggers apoptotic or necroptotic cell death[J].Sci Rep,2018,8(1):17862.
[25]Cai Q,Sun H,Peng Y,et al.A potent and orally active antagonist(SM-406/AT-406)of multiple inhibitor of apoptosis proteins(IAPs)in clinical development for cancer treatment[J].J Med Chem,2011,54(8):2714-2726.
[26]Wong H,Budha NR,West K,et al.Dogs are more sensitive to antagonists of inhibitor of apoptosis proteins than rats and humans:a translational toxicokinetic/toxicodynamic analysis[J].Toxicol Sci,2012,130(1):205-213.
[27]Flygare JA,Beresini M,Budha N,et al.Discovery of a potent smallmolecule antagonist of inhibitor of apoptosis(IAP)proteins and clinical candidate for the treatment of cancer(GDC-0152)[J].J Med Chem,2012,55(9):4101-4113.
[28]Tolcher AW,Bendell JC,Papadopoulos KP,et al.A Phase IDose-escalation study evaluating the safety tolerability and pharmacokinetics of CUDC-427,a potent,oral,monovalent IAPantagonist,in patients with refractory solid tumors[J].Clin Cancer Res,2016,22(18):4567-4573.
[29]Sikic BI,Eckhardt SG,Gallant G,et al.Safety,pharmacokinetics(PK),and pharmacodynamics(PD)of HGS1029,an inhibitor of apoptosis protein(IAP)inhibitor,in patients(Pts)with advanced solid tumors:Results of a phase I study[J].J Clin Oncol,2011,29(15):3008.
[30]Amaravadi RK,Schilder RJ,Martin LP,et al.A Phase 1 Study of the Smac-mimetic Birinapant in adults with refractory solid tumors or lymphoma[J].Mol Cancer Ther,2015,14(11):2569-2575.
[31]Lu J,Rong S,Sun H,et al.A potent and highly efficacious bivalent Smac mimetic APG-1387 in Phase I clinical development[J].Eur J Canc,2014,50(6):89.
[32]Wang J,Li W.Discovery of novel second mitochondria-derived activator of Caspase mimetics as selective inhibitor of apoptosis protein inhibitors[J].J Pharmacol Exp Ther,2014,349(2):319-329.
[33]Ling X,Hegab T,Hangauer D,Li FZ.A novel compound(DH-XP-0090)designed as an IAP antagonist shows inhibition of both survivin expression and tumor cell growth accompanied with caspase activation and apoptosis[C].San Diego,CA,99th AACRAnnual Meeting,2008:4.
[34]Ebert G,Allison C,Preston S,et al.Eliminating hepatitis B by antagonizing cellular inhibitors of apoptosis[J].Proc Natl Acad Sci US A,2015,112(18):5803-5808.
[2]Salvesen GS,Duckett CS.IAP proteins:blocking the road to death's door[J].Nat Rev Mol Cell Biol,2002,3(6):401-410.
[3]Hunter AM,La Casse EC,Korneluk RG.The inhibitors of apoptosis(IAPs)as cancer targets[J].Apoptosis,2007,12(9):1543-1568.
[4]Crook NE,Clem RJ,Miller LK.An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif[J].J Virol,1993,67(4):2168-2174.
[5]LaCasse EC,Beug ST,Korneluk RG.The inhibitors of apoptosis(IAPs):Over 20 years of research into life and death[J].Semin Cell Dev Biol,2015,39:70-71.
[6]Gyrd-Hansen M,Meier P.IAPs:from caspase inhibitors to modulators of NF-kappaB,inflammation and cancer[J].Nat Rev Cancer,2010,10(8):561-574.
[7]Samuel T,Welsh K,Lober T,et al.Distinct BIR domains of cIAP1mediate binding to and ubiquitination of tumor necrosis factor receptor-associated factor 2 and second mitochondrial activator of caspases[J].J Biol Chem,2006,281(2):1080-1090.
[8]Varfolomeev E,Blankenship JW,Wayson SM,et al.IAPantagonists induce autoubiquitination of c-IAPs,NF-kappaBactivation,and TNFalpha-dependent apoptosis[J].Cell,2007,131(4):669-681.
[9]Vince JE,Wong WW,Khan N,et al.IAP antagonists target cIAP1to induce TNFalpha-dependent apoptosis[J].Cell,2007,131(4):682-693.
[10]Bai L,Smith DC,Wang S.Small-molecule SMAC mimetics as new cancer therapeutics[J].Pharmacol Ther,2014,144(1):82-95.
[11]Qiu W,Liu H,Sebastini A,et al.An apoptosis-independent role of SMAC in tumor suppression[J].Oncogene,2013,32(19):2380-2389.
[12]Hashimoto K,Saito B,Miyamoto N,et al.Design and synthesis of potent inhibitor of apoptosis(IAP)proteins antagonists bearing an octahydropyrrolo[1,2-a]pyrazine scaffold as a novel proline mimetic[J].J Med Chem,2013,56(3):1228-1246.
[13]Sumi H,Yabuki M,Iwai K,et al.Antitumor activity and pharmacodynamic biomarkers of a novel and orally available smallmolecule antagonist of inhibitor of apoptosis proteins[J].Mol Cancer Ther,2013,12(2):230-240.
[14]Zobel K,Wang L,Varfolomeev E,et al.Design,synthesis,and biological activity of a potent Smac mimetic that sensitizes cancer cells to apoptosis by antagonizing IAPs[J].ACS Chem Biol,2006,1(8):525-533.
[15]Cossu F,Malvezzi F,Canevari G,et al.Recognition of Smac-mimetic compounds by the BIR domain of cIAP1[J].Protein Sci,2010,19(12):2418-2429.
[16]Silke J,Meier P.Inhibitor of apoptosis(IAP)proteinsmodulators of cell death and inflammation[J].Cold Spring Harb Perspect Biol,2013,5(2):a008730.
[17]Weisberg E,Ray A,Barrett R,et al.Smac mimetics:implications for enhancement of targeted therapies in leukemia[J].Leukemia,2010,24(12):2100-2109.
[18]Chen KF,Lin JP,Shiau CW,et al.Inhibition of Bcl-2 improves effect of LCL161,a SMAC mimetic,in hepatocellular carcinoma cells[J].Biochem Pharmacol,2012,84(3):268-277.
[19]Bardia A,Parton M,Kümmel S,et al.Paclitaxel With Inhibitor of Apoptosis Antagonist,LCL161,for Localized Triple-Negative Breast Cancer,Prospectively Stratified by Gene Signature in a Biomarker-Driven Neoadjuvant Trial[J].J Clin Oncol,2018:JCO2017748392.
[20]La Casse EC,Mahoney DJ,Cheung HH,et al.IAP-targeted therapies for cancer[J].Oncogene,2008,27(48):6252-6275.
[21]Ward GA,Lewis EJ,Ahn JS,et al.ASTX660,a Novel Non-peptidomimetic Antagonist of cIAP1/2 and XIAP,Potently Induces TNFα-Dependent Apoptosis in Cancer Cell Lines and Inhibits Tumor Growth[J].Mol Cancer Ther,2018,17(7):1381-1391.
[22]Johnson CN,Ahn JS,Buck IM,et al.A Fragment-Derived Clinical Candidate for Antagonism of X-Linked and Cellular Inhibitor of Apoptosis Proteins:1-(6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl)-2-[(2 R,5R)-5-methyl-2-([(3R)-3-methylmorpholin-4-yl]methyl)piperazin-1-yl]ethan-1-one(ASTX660)[J].J Med Chem,2018,61(16):7314-7329.
[23]Hurwitz HI,Smith DC,Pitot HC,et al.Safety,pharmacokinetics,and pharmacodynamic properties of oral DEBIO1143(AT-406)in patients with advanced cancer:results of a first-in-man study[J].Cancer Chemother Pharmacol,2015,75(4):851-859.
[24]Thibault B,Genre L,Le Naour A,etal.DEBIO 1143,an IAPinhibitor,reverses carboplatin resistance in ovarian cancer cells and triggers apoptotic or necroptotic cell death[J].Sci Rep,2018,8(1):17862.
[25]Cai Q,Sun H,Peng Y,et al.A potent and orally active antagonist(SM-406/AT-406)of multiple inhibitor of apoptosis proteins(IAPs)in clinical development for cancer treatment[J].J Med Chem,2011,54(8):2714-2726.
[26]Wong H,Budha NR,West K,et al.Dogs are more sensitive to antagonists of inhibitor of apoptosis proteins than rats and humans:a translational toxicokinetic/toxicodynamic analysis[J].Toxicol Sci,2012,130(1):205-213.
[27]Flygare JA,Beresini M,Budha N,et al.Discovery of a potent smallmolecule antagonist of inhibitor of apoptosis(IAP)proteins and clinical candidate for the treatment of cancer(GDC-0152)[J].J Med Chem,2012,55(9):4101-4113.
[28]Tolcher AW,Bendell JC,Papadopoulos KP,et al.A Phase IDose-escalation study evaluating the safety tolerability and pharmacokinetics of CUDC-427,a potent,oral,monovalent IAPantagonist,in patients with refractory solid tumors[J].Clin Cancer Res,2016,22(18):4567-4573.
[29]Sikic BI,Eckhardt SG,Gallant G,et al.Safety,pharmacokinetics(PK),and pharmacodynamics(PD)of HGS1029,an inhibitor of apoptosis protein(IAP)inhibitor,in patients(Pts)with advanced solid tumors:Results of a phase I study[J].J Clin Oncol,2011,29(15):3008.
[30]Amaravadi RK,Schilder RJ,Martin LP,et al.A Phase 1 Study of the Smac-mimetic Birinapant in adults with refractory solid tumors or lymphoma[J].Mol Cancer Ther,2015,14(11):2569-2575.
[31]Lu J,Rong S,Sun H,et al.A potent and highly efficacious bivalent Smac mimetic APG-1387 in Phase I clinical development[J].Eur J Canc,2014,50(6):89.
[32]Wang J,Li W.Discovery of novel second mitochondria-derived activator of Caspase mimetics as selective inhibitor of apoptosis protein inhibitors[J].J Pharmacol Exp Ther,2014,349(2):319-329.
[33]Ling X,Hegab T,Hangauer D,Li FZ.A novel compound(DH-XP-0090)designed as an IAP antagonist shows inhibition of both survivin expression and tumor cell growth accompanied with caspase activation and apoptosis[C].San Diego,CA,99th AACRAnnual Meeting,2008:4.
[34]Ebert G,Allison C,Preston S,et al.Eliminating hepatitis B by antagonizing cellular inhibitors of apoptosis[J].Proc Natl Acad Sci US A,2015,112(18):5803-5808.