Small Molecule that Reverses Dexamethasone Resistance in T-cell Acute Lymphoblastic Leukemia (T-ALL)

被引：12

作者：

Cantley, Alexandra M. ^{[1
]}

Welsch, Matthew ^{[2
]}

Ambesi-Impiombato, Alberto ^{[5
]}

Sanchez-Martin, Marta ^{[5
]}

Kim, Mi-Yeon ^{[5
]}

Bauer, Andras ^{[1
]}

Ferrando, Adolfo ^{[5
,6
,7
]}

Stockwell, Brent R. ^{[1
,2
,3
,4
]}

机构：

[1] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA

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

[3] Columbia Univ, Howard Hughes Med Inst, New York, NY 10027 USA

[4] Columbia Univ, Med Ctr, Dept Syst Biol, New York, NY 10032 USA

[5] Columbia Univ, Inst Canc Genet, New York, NY 10032 USA

[6] Columbia Univ, Dept Pathol, New York, NY 10032 USA

[7] Columbia Univ, Dept Pediat, New York, NY 10032 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2014年 / 5卷 / 07期

基金：

美国国家卫生研究院;

关键词：

T-cell acute lymphoblastic leukemia; dexamethasone; glucocorticoid resistance; NOTCH1; GLUCOCORTICOID-INDUCED APOPTOSIS; GAMMA-SECRETASE INHIBITORS; SOLUBILITY; EXPRESSION; RECEPTOR; LINEAGE; NOTCH1; SET;

D O I：

10.1021/ml500044g

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Glucocorticoids are one of the most utilized and effective therapies in treating T-cell acute lymphoblastic leukemia. However, patients often develop resistance to glucocorticoids, rendering these therapies ineffective. We screened 9517 compounds, selected for their lead-like properties, chosen from among 3 372 615 compounds, against a dexamethasone-resistant T-ALL cell line to identify small molecules that reverse glucocorticoid resistance. We synthesized analogues of the most effective compound, termed J9, from the screen in order to define the scaffold's structure activity relationship. Active compounds restored sensitivity to glucocorticoids through upregulation of the glucocorticoid receptor. This compound and mechanism may provide a strategy for overcoming glucocorticoid resistance in patients with T-ALL.

引用

页码：754 / 759

页数：6

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