Inhibition of bromodomain-containing protein 9 for the prevention of epigenetically-defined drug resistance

被引：30

作者：

Crawford, Terry D. ^{[1
]}

Vartanian, Steffan ^{[1
]}

Cote, Alexandre ^{[2
]}

Bellon, Steve ^{[2
]}

Duplessis, Martin ^{[2
]}

Flynn, E. Megan ^{[1
]}

Hewitt, Michael ^{[2
]}

Huang, Hon-Ren ^{[2
]}

Kiefer, James R. ^{[1
]}

Murray, Jeremy ^{[1
]}

Nasveschuk, Christopher G. ^{[2
]}

Pardo, Eneida ^{[2
]}

Romero, F. Anthony ^{[1
]}

Sandy, Peter ^{[2
]}

Tang, Yong ^{[2
]}

Taylor, Alexander M. ^{[2
]}

Tsui, Vickie ^{[1
]}

Wang, Jian ^{[3
]}

Wang, Shumei ^{[1
]}

Zawadzke, Laura ^{[2
]}

Albrecht, Brian K. ^{[2
]}

Magnuson, Steven R. ^{[1
]}

Cochran, Andrea G. ^{[1
]}

Stokoe, David ^{[1
]}

机构：

[1] Genentech Inc, 1 DNA Way, San Francisco, CA 94080 USA

[2] Constellat Pharmaceut, 215 First St,Suite 200, Cambridge, MA 02142 USA

[3] Wuxi Apptec Co Ltd, 288 Fute Zhong Rd, Shanghai 200131, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2017年 / 27卷 / 15期

关键词：

Epigenetics; Bromodomain; BRD9; Inhibitor; Resistance; SELECTIVE INHIBITORS; CANCER; CELLS; BRD9; HISTONE; TARGET; ACETYLATION; RECOGNITION; COMPLEXES; DESIGN;

D O I：

10.1016/j.bmcl.2017.05.063

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Bromodomain-containing protein 9 (BRD9), an epigenetic "reader" of acetylated lysines on post-translationally modified histone proteins, is upregulated in multiple cancer cell lines. To assess the functional role of BRD9 in cancer cell lines, we identified a small-molecule inhibitor of the BRD9 bromodomain. Starting from a pyrrolopyridone lead, we used structure-based drug design to identify a potent and highly selective in vitro tool compound 11, (GNE-375). While this compound showed minimal effects in cell viability or gene expression assays, it showed remarkable potency in preventing the emergence of a drug tolerant population in EGFR mutant PC9 cells treated with EGFR inhibitors. Such tolerance has been linked to an altered epigenetic state, and 11 decreased BRD9 binding to chromatin, and this was associated with decreased expression of ALDH1A1, a gene previously shown to be important in drug tolerance. BRD9 inhibitors may therefore show utility in preventing epigenetically-defined drug resistance. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：3534 / 3541

页数：8

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