Inhibition of Bfl-1 with N-aryl maleimides

被引：23

作者：

Cashman, John R. ^{[1
]}

MacDonald, Mary ^{[1
]}

Ghirmai, Senait ^{[1
]}

Okolotowicz, Karl J. ^{[1
]}

Sergienko, Eduard ^{[2
]}

Brown, Brock ^{[2
]}

Garcia, Xochella ^{[2
]}

Zhai, Dayong ^{[2
]}

Dahl, Russell ^{[2
]}

Reed, John C. ^{[2
]}

机构：

[1] Human BioMol Res Inst, San Diego, CA 92121 USA

[2] Sanford Burnham Inst Med Res, La Jolla, CA 92037 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 22期

关键词：

Bfl-1; inhibitors; N-Aryl maleimides; High-throughput screening; Anti-cancer agents; BCL-2 FAMILY PROTEINS; POLYPHENOLS; APOPTOSIS;

D O I：

10.1016/j.bmcl.2010.09.046

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

High-throughput screening of 66,000 compounds using competitive binding of peptides comprising the BH3 domain to anti-apoptotic Bfl-1 led to the identification of 14 validated 'hits' as inhibitors of Bfl-1. N-Aryl maleimide 1 was among the validated 'hits'. A chemical library encompassing over 280 analogs of 1 was prepared following a two-step synthesis. Structure-activity studies for inhibition of Bfl-1 by analogs of N-aryl maleimide 1 revealed a preference for electron-withdrawing substituents in the N-aryl ring and hydrophilic amines appended to the maleimide core. Inhibitors of Bfl-1 are potential development candidates for anti-cancer therapeutics. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：6560 / 6564

页数：5

共 19 条

[1] The landscape of somatic copy-number alteration across human cancers [J].

Beroukhim, Rameen ;

Mermel, Craig H. ;

Porter, Dale ;

Wei, Guo ;

Raychaudhuri, Soumya ;

Donovan, Jerry ;

Barretina, Jordi ;

Boehm, Jesse S. ;

Dobson, Jennifer ;

Urashima, Mitsuyoshi ;

Mc Henry, Kevin T. ;

Pinchback, Reid M. ;

Ligon, Azra H. ;

Cho, Yoon-Jae ;

Haery, Leila ;

Greulich, Heidi ;

Reich, Michael ;

Winckler, Wendy ;

Lawrence, Michael S. ;

Weir, Barbara A. ;

Tanaka, Kumiko E. ;

Chiang, Derek Y. ;

Bass, Adam J. ;

Loo, Alice ;

Hoffman, Carter ;

Prensner, John ;

Liefeld, Ted ;

Gao, Qing ;

Yecies, Derek ;

Signoretti, Sabina ;

Maher, Elizabeth ;

Kaye, Frederic J. ;

Sasaki, Hidefumi ;

Tepper, Joel E. ;

Fletcher, Jonathan A. ;

Tabernero, Josep ;

Baselga, Jose ;

Tsao, Ming-Sound ;

Demichelis, Francesca ;

Rubin, Mark A. ;

Janne, Pasi A. ;

Daly, Mark J. ;

Nucera, Carmelo ;

Levine, Ross L. ;

Ebert, Benjamin L. ;

Gabriel, Stacey ;

Rustgi, Anil K. ;

Antonescu, Cristina R. ;

Ladanyi, Marc ;

Letai, Anthony .

NATURE, 2010, 463 (7283) :899-905

[2] Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function [J].

Chen, L ;

Willis, SN ;

Wei, A ;

Smith, BJ ;

Fletcher, JI ;

Hinds, MG ;

Colman, PM ;

Day, CL ;

Adams, JM ;

Huang, DCS .

MOLECULAR CELL, 2005, 17 (03) :393-403

[3] Solution structure of prosurvival Mcl-1 and characterization of its binding by proapoptotic BH3-only ligands [J].

Day, CL ;

Chen, L ;

Richardson, SJ ;

Harrison, PJ ;

Huang, DCS ;

Hinds, MG .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (06) :4738-4744

[4] Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL [J].

Degterev, A ;

Lugovskoy, A ;

Cardone, M ;

Mulley, B ;

Wagner, G ;

Mitchison, T ;

Yuan, JY .

NATURE CELL BIOLOGY, 2001, 3 (02) :173-182

[5] Some synthetic applications of 2,3-dichloro-N-phenylmaleimide:: A novel synthesis of 2-phenylpyrrolo[3,4-b]quinoxaline-1,3-diones.: I [J].

Hanaineh-Abdelnour, L ;

Bayyuk, S ;

Theodorie, R .

TETRAHEDRON, 1999, 55 (40) :11859-11870

[6] Survival activity of Bcl-2 homologs Bcl-w and A1 only partially correlates with their ability to bind pro-apoptotic family members [J].

Holmgreen, SP ;

Huang, DCS ;

Adams, JM ;

Cory, S .

CELL DEATH AND DIFFERENTIATION, 1999, 6 (06) :525-532

[7] Apoptosis: A link between cancer genetics and chemotherapy [J].

Johnstone, RW ;

Ruefli, AA ;

Lowe, SW .

CELL, 2002, 108 (02) :153-164

[8]

KITADA S, 2003, J MED CHEM, P46

[9] BH3 domains of BH3-only proteins differentially regulate bax-mediated mitochondrial membrane permeabilization both directly and indirectly [J].

Kuwana, T ;

Bouchier-Hayes, L ;

Chipuk, JE ;

Bonzon, C ;

Sullivan, BA ;

Green, DR ;

Newmeyer, DD .

MOLECULAR CELL, 2005, 17 (04) :525-535

[10] NF-κB-mediated up-regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes [J].

Lee, HH ;

Dadgostar, H ;

Cheng, QW ;

Shu, JY ;

Cheng, GH .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (16) :9136-9141

← 1 2 →