A small molecule Smac mimic potentiates TRAIL- and TNFα-mediated cell death

被引：572
作者：
Li, L
Thomas, RM
Suzuki, H
De Brabander, JK
Wang, XD
Harran, PG
机构：
[1] Univ Texas, SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA
[2] Univ Texas, SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA
来源：
SCIENCE | 2004年 / 305卷 / 5689期
关键词：
D O I：
10.1126/science.1098231
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
We describe the synthesis and properties of a small molecule mimic of Smac, a pro-apoptotic protein that functions by relieving inhibitor-of-apoptosis protein (IAP)-mediated suppression of caspase activity. The compound binds to X chromosome-encoded IAP (XIAP), cellular IAP 1 (clAP-1), and cellular IAP 2 (clAP-2) and synergizes with both tumor necrosis factor alpha (TNFalpha.) and TNF-related apoptosis-inducing ligand (TRAIL) to potently induce caspase activation and apoptosis in human cancer cells. The molecule has allowed a temporal, unbiased evaluation of the roles that IAP proteins play during signaling from TRAIL and TNF receptors. The compound is also a lead structure for the development of IAP antagonists potentially useful as therapy for cancer and inflammatory diseases.
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收藏
页码：1471 / 1474
页数：4
相关论文
共 25 条
[1]   Synthetic Smac/DIABLO peptides enhance the effects of chemotherapeutic agents by binding XIAP and cIAP1 in situ [J].
Arnt, CR ;
Chiorean, MV ;
Heldebrant, MV ;
Gores, GJ ;
Kaufmann, SH .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (46) :44236-44243
[2]  
BERSCHEID R, 1992, SYNTHESIS-STUTTGART, P58
[3]   Structural and biochemical basis of apoptotic activation by Smac/DIABLO [J].
Chai, JJ ;
Du, CY ;
Wu, JW ;
Kyin, S ;
Wang, XD ;
Shi, YG .
NATURE, 2000, 406 (6798) :855-862
[4]   Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-kappa B control [J].
Chu, ZL ;
McKinsey, TA ;
Liu, L ;
Gentry, JJ ;
Malim, MH ;
Ballard, DW .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (19) :10057-10062
[5]   A JNK-dependent pathway is required for TNFα-induced apoptosis [J].
Deng, YB ;
Ren, XY ;
Yang, L ;
Lin, YH ;
Wu, XW .
CELL, 2003, 115 (01) :61-70
[6]   IAP family proteins - suppressors of apoptosis [J].
Deveraux, QL ;
Reed, TC .
GENES & DEVELOPMENT, 1999, 13 (03) :239-252
[7]   Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition [J].
Du, CY ;
Fang, M ;
Li, YC ;
Li, L ;
Wang, XD .
CELL, 2000, 102 (01) :33-42
[8]   Cytokine blockade as a new strategy to treat rheumatoid arthritis -: Inhibition of tumor necrosis factor [J].
Fox, DA .
ARCHIVES OF INTERNAL MEDICINE, 2000, 160 (04) :437-444
[9]   Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo [J].
Fulda, S ;
Wick, W ;
Weller, M ;
Debatin, KM .
NATURE MEDICINE, 2002, 8 (08) :808-815
[10]   Expression of the inhibitor of apoptosis (IAP) family members in human neutrophils: up-regulation of cIAP2 by granulocyte colony-stimulating factor and overexpression of cIAP2 in chronic neutrophilic leukemia [J].
Hasegawa, T ;
Suzuki, K ;
Sakamoto, C ;
Ohta, K ;
Nishiki, S ;
Hino, M ;
Tatsumi, N ;
Kitagawa, S .
BLOOD, 2003, 101 (03) :1164-1171
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