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凋亡抑制蛋白（IAP）作为癌症治疗的药物靶点。

Inhibitor of Apoptosis (IAP) proteins as drug targets for the treatment of cancer.

作者信息

Vaux David L

机构信息

Department of Biochemistry, La Trobe University Plenty Road, Bundoora 3086 Victoria Australia.

出版信息

F1000 Biol Rep. 2009 Oct 29;1:79. doi: 10.3410/B1-79.

DOI:10.3410/B1-79
PMID:20948609
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2948278/
Abstract

Three companies, Genentech, Aegera Therapeutics/Human Genome Sciences, and Novartis, have commenced phase 1 clinical trials of inhibitor of apoptosis (IAP) antagonist 'Smac mimetic' compounds for the treatment of cancer. These trials represent the culmination of a line of research that commenced with analysis of how insect viruses stop host cells from killing themselves and led to the discovery of a family of proteins that regulate development in insects and signalling by tumour necrosis factor superfamily members in mammals, which prompted development of drugs that mimic natural IAP-binding proteins to promote cell death.

摘要

基因泰克公司、艾格拉治疗公司/人类基因组科学公司和诺华公司这三家公司已开始针对凋亡抑制蛋白（IAP）拮抗剂“Smac模拟物”化合物开展1期癌症治疗临床试验。这些试验代表了一系列研究的成果，该研究始于对昆虫病毒如何阻止宿主细胞自我死亡的分析，并由此发现了一类调节昆虫发育以及哺乳动物中肿瘤坏死因子超家族成员信号传导的蛋白质家族，这促使研发出模仿天然IAP结合蛋白以促进细胞死亡的药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a08f/2948278/aec97e7966fe/1757-594X-0001-0000000079-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a08f/2948278/485bed540244/1757-594X-0001-0000000079-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a08f/2948278/3c83c62a731d/1757-594X-0001-0000000079-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a08f/2948278/6d9a670adb68/1757-594X-0001-0000000079-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a08f/2948278/aec97e7966fe/1757-594X-0001-0000000079-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a08f/2948278/485bed540244/1757-594X-0001-0000000079-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a08f/2948278/3c83c62a731d/1757-594X-0001-0000000079-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a08f/2948278/6d9a670adb68/1757-594X-0001-0000000079-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a08f/2948278/aec97e7966fe/1757-594X-0001-0000000079-g004.jpg

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本文引用的文献

1
XIAP discriminates between type I and type II FAS-induced apoptosis.X连锁凋亡抑制蛋白可区分I型和II型FAS诱导的细胞凋亡。
Nature. 2009 Aug 20;460(7258):1035-9. doi: 10.1038/nature08229. Epub 2009 Jul 22.
2
Antagonism of c-IAP and XIAP proteins is required for efficient induction of cell death by small-molecule IAP antagonists.小分子IAP拮抗剂有效诱导细胞死亡需要c-IAP和XIAP蛋白的拮抗作用。
ACS Chem Biol. 2009 Jul 17;4(7):557-66. doi: 10.1021/cb900083m.
3
Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2.
X 连锁凋亡抑制蛋白调控肺成纤维细胞抵抗 Fas 介导的凋亡。
Am J Respir Cell Mol Biol. 2013 Jul;49(1):86-95. doi: 10.1165/rcmb.2012-0224OC.
4
Fas death receptor signalling: roles of Bid and XIAP.Fas 死亡受体信号转导：Bid 和 XIAP 的作用。
Cell Death Differ. 2012 Jan;19(1):42-50. doi: 10.1038/cdd.2011.121. Epub 2011 Sep 30.
细胞凋亡抑制蛋白cIAP1和cIAP2是模式识别受体NOD1和NOD2进行天然免疫信号传导所必需的。
Immunity. 2009 Jun 19;30(6):789-801. doi: 10.1016/j.immuni.2009.04.011. Epub 2009 May 21.
4
The E3 ubiquitin ligase cIAP1 binds and ubiquitinates caspase-3 and -7 via unique mechanisms at distinct steps in their processing.E3泛素连接酶cIAP1通过独特机制在半胱天冬酶-3和-7加工过程的不同步骤对其进行结合并使其泛素化。
J Biol Chem. 2009 May 8;284(19):12772-82. doi: 10.1074/jbc.M807550200. Epub 2009 Mar 3.
5
IAP-targeted therapies for cancer.针对癌症的IAP靶向疗法。
Oncogene. 2008 Oct 20;27(48):6252-75. doi: 10.1038/onc.2008.302.
6
IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-kappaB as well as cell survival and oncogenesis.凋亡抑制蛋白含有一个进化上保守的泛素结合结构域，该结构域可调节核因子κB以及细胞存活和肿瘤发生。
Nat Cell Biol. 2008 Nov;10(11):1309-17. doi: 10.1038/ncb1789. Epub 2008 Oct 19.
7
Structures of the cIAP2 RING domain reveal conformational changes associated with ubiquitin-conjugating enzyme (E2) recruitment.cIAP2 环指结构域的结构揭示了与泛素结合酶（E2）募集相关的构象变化。
J Biol Chem. 2008 Nov 14;283(46):31633-40. doi: 10.1074/jbc.M804753200. Epub 2008 Sep 10.
8
Both cIAP1 and cIAP2 regulate TNFalpha-mediated NF-kappaB activation.细胞凋亡抑制蛋白1（cIAP1）和细胞凋亡抑制蛋白2（cIAP2）均调节肿瘤坏死因子α（TNFα）介导的核因子κB（NF-κB）激活。
Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11778-83. doi: 10.1073/pnas.0711122105. Epub 2008 Aug 12.
9
c-IAP1 and c-IAP2 are critical mediators of tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB activation.细胞凋亡抑制蛋白1（c-IAP1）和细胞凋亡抑制蛋白2（c-IAP2）是肿瘤坏死因子α（TNFα）诱导的核因子κB（NF-κB）激活的关键介质。
J Biol Chem. 2008 Sep 5;283(36):24295-9. doi: 10.1074/jbc.C800128200. Epub 2008 Jul 11.
10
cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination.cIAP1和cIAP2作为促进RIP1泛素化的E3连接酶发挥作用，从而促进癌细胞存活。
Mol Cell. 2008 Jun 20;30(6):689-700. doi: 10.1016/j.molcel.2008.05.014.