Design, Synthesis, and Evaluation of Tricyclic, Conformationally Constrained Small-Molecule Mimetics of Second Mitochondria-Derived Activator of Caspases

被引：32

作者：

Zhang, Bin ^{[2
]}

Nikolovska-Coleska, Zaneta ^{[1
,3
]}

Zhang, Yan ^{[2
]}

Bai, Longchuan ^{[1
,3
]}

Qiu, Su ^{[1
,3
]}

Yang, Chao-Yie ^{[1
,3
]}

Sun, Haiying ^{[1
,3
]}

Wang, Shaomeng ^{[1
,3
,4
,5
]}

Wu, Yikang ^{[2
]}

机构：

[1] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA

[2] Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Bioorgan & Nat Prod Chem, Shanghai 200032, Peoples R China

[3] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 23期

基金：

美国国家卫生研究院; 中国国家自然科学基金;

关键词：

D O I：

10.1021/jm801146d

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of tricyclic, conformationally constrained Smac mimetics have been designed, synthesized, and evaluated. The most potent compound 6 (WS-5) binds to XIAP, cIAP-1, and cIAP-2 with K-i of 18, 1.1, and 4.2 nM, respectively. Compound 6 antagonizes XIAP in a functional assay, induces cIAP-1 degradation, inhibits cell growth with an IC50 of 68 nM in the MDA-MB-231 cancer cell line, and effectively induces cancer cells to undergo apoptosis.

引用

页码：7352 / 7355

页数：4

共 26 条

[1] IAP family proteins - suppressors of apoptosis [J].

Deveraux, QL ;

Reed, TC .

GENES & DEVELOPMENT, 1999, 13 (03) :239-252

[2] 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

[3] AN ACYL-IMINIUM ION CYCLIZATION ROUTE TO A NOVEL CONFORMATIONALLY RESTRICTED DIPEPTIDE MIMIC - APPLICATIONS TO ANGIOTENSIN-CONVERTING ENZYME-INHIBITION [J].

FLYNN, GA ;

GIROUX, EL ;

DAGE, RC .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1987, 109 (25) :7914-7915

[4] Inhibitor of apoptosis proteins as targets for anticancer therapy [J].

Fuldo, Simone .

EXPERT REVIEW OF ANTICANCER THERAPY, 2007, 7 (09) :1255-1264

[5] XIAP: Apoptotic brake and promising therapeutic target [J].

Holcik, M ;

Gibson, H ;

Korneluk, RG .

APOPTOSIS, 2001, 6 (04) :253-261

[6] A small molecule Smac mimic potentiates TRAIL- and TNFα-mediated cell death [J].

Li, L ;

Thomas, RM ;

Suzuki, H ;

De Brabander, JK ;

Wang, XD ;

Harran, PG .

SCIENCE, 2004, 305 (5689) :1471-1474

[7] Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain [J].

Liu, ZH ;

Sun, CH ;

Olejniczak, ET ;

Meadows, RP ;

Betz, SF ;

Oost, T ;

Herrmann, J ;

Wu, JC ;

Fesik, SW .

NATURE, 2000, 408 (6815) :1004-1008

[8] Apoptosis in cancer [J].

Lowe, SW ;

Lin, AW .

CARCINOGENESIS, 2000, 21 (03) :485-495

[9] Development and optimization of a binding assay for the XIAP BIR3 domain using fluorescence polarization [J].

Nikolovska-Coleska, Z ;

Wang, RX ;

Fang, XL ;

Pan, HG ;

Tomita, Y ;

Li, P ;

Roller, PP ;

Krajewski, K ;

Saito, NG ;

Stuckey, JA ;

Wang, SM .

ANALYTICAL BIOCHEMISTRY, 2004, 332 (02) :261-273

[10] Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer [J].

Oost, TK ;

Sun, CH ;

Armstrong, RC ;

Al-Assaad, AS ;

Betz, SF ;

Deckwerth, TL ;

Ding, H ;

Elmore, SW ;

Olejniczak, ET ;

Oleksijew, A ;

Oltersdorf, T ;

Rosenberg, SH ;

Shoemaker, AR ;

Tomaselli, KJ ;

Zou, H ;

Fesik, SW .

JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (18) :4417-4426

← 1 2 3 →