A Small-Molecule Inhibitor of BCL6 Kills DLBCL Cells In Vitro and In Vivo

被引：235

作者：

Cerchietti, Leandro C. ^{[2
,5
]}

Ghetu, Alexandru F. ^{[3
,4
]}

Zhu, Xiao ^{[1
]}

Da Silva, Gustavo F. ^{[6
]}

Zhong, Shijun ^{[1
]}

Matthews, Marilyn ^{[1
]}

Bunting, Karen L. ^{[2
,5
]}

Polo, Jose M. ^{[6
]}

Fares, Christophe ^{[3
,4
]}

Arrowsmith, Cheryl H. ^{[3
,4
,7
]}

Yang, Shao Ning ^{[2
,5
]}

Garcia, Monica ^{[2
,5
]}

Coop, Andrew ^{[1
]}

MacKerell, Alexander D., Jr. ^{[1
]}

Prive, Gilbert G. ^{[3
,4
,7
,8
]}

Melnick, Ari ^{[2
,5
]}

机构：

[1] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA

[2] Cornell Univ, Weill Cornell Med Coll, Dept Pharmacol, New York, NY 10065 USA

[3] Ontario Canc Inst, Toronto, ON M5G 1L7, Canada

[4] Campbell Family Inst Canc Res, Toronto, ON M5G 1L7, Canada

[5] Cornell Univ, Weill Cornell Med Coll, Div Hematol & Med Oncol, Dept Med, New York, NY 10065 USA

[6] Albert Einstein Coll Med, Dept Dev & Mol Biol, Bronx, NY 10461 USA

[7] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2N9, Canada

[8] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada

来源：

CANCER CELL | 2010年 / 17卷 / 04期

关键词：

GERMINAL-CENTER FORMATION; BTB DOMAIN; EXPRESSION; PHARMACOKINETICS; IDENTIFICATION; DOCKING; COREPRESSOR; MODEL; AZITHROMYCIN; PATHOGENESIS;

D O I：

10.1016/j.ccr.2009.12.050

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The BCL6 transcriptional repressor is the most frequently involved oncogene in diffuse large B cell lymphoma (DLBCL). We combined computer-aided drug design with functional assays to identify low-molecular-weight compounds that bind to the corepressor binding groove of the BCL6 BTB domain. One such compound disrupted BCL6/corepressor complexes in vitro and in vivo, and was observed by X-ray crystallography and NMR to bind the critical site within the BIB groove. This compound could induce expression of BCL6 target genes and kill BCL6-positive DLBCL cell lines. In xenotransplantation experiments, the compound was nontoxic and potently suppressed DLBCL tumors in vivo. The compound also killed primary DLBCLs from human patients.

引用

页码：400 / 411

页数：12

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