Development of small-molecule probes that selectively kill cells induced to express mutant RAS

被引：189

作者：

Weiwer, Michel ^{[1
]}

Bittker, Joshua A. ^{[1
]}

Lewis, Timothy A. ^{[1
]}

Shimada, Kenichi ^{[2
,3
]}

Yang, Wan Seok ^{[2
,3
]}

MacPherson, Lawrence ^{[1
]}

Dandapani, Sivaraman ^{[1
]}

Palmer, Michelle ^{[1
]}

Stockwell, Brent R. ^{[2
,3
]}

Schreiber, Stuart L. ^{[1
,4
]}

Munoz, Benito ^{[1
]}

机构：

[1] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[2] Columbia Univ, Dept Biol Sci, Howard Hughes Med Inst, New York, NY 10027 USA

[3] Columbia Univ, Dept Chem, New York, NY 10027 USA

[4] Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 04期

关键词：

RAS oncogene; Synthetic lethal; alpha-Chloroamide; Nitroisoxazole; MLPCN probes; SYNTHETIC LETHAL INTERACTIONS; HUMAN TUMOR-CELLS; CANCER-CELLS; K-RAS; IDENTIFICATION; VIRUS;

D O I：

10.1016/j.bmcl.2011.09.047

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Synthetic lethal screening is a chemical biology approach to identify small molecules that selectively kill oncogene-expressing cell lines with the goal of identifying pathways that provide specific targets against cancer cells. We performed a high-throughput screen of 303,282 compounds from the National Institutes of Health-Molecular Libraries Small Molecule Repository (NIH-MLSMR) against immortalized BJ fibroblasts expressing HRAS(G12V) followed by a counterscreen of lethal compounds in a series of isogenic cells lacking the HRAS(G12V) oncogene. This effort led to the identification of two novel molecular probes (PubChem CID 3689413, ML162 and CID 49766530, ML210) with nanomolar potencies and 4-23-fold selectivities, which can potentially be used for identifying oncogene-specific pathways and targets in cancer cells. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：1822 / 1826

页数：5

共 18 条

[1] STK33 Kinase Activity Is Nonessential in KRAS-Dependent Cancer Cells [J].