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

Alexandra M Cantley; Matthew Welsch; Alberto Ambesi-Impiombato; Marta Sanchez-Martin; Mi-Yeon Kim; Andras Bauer; Adolfo Ferrando; Brent R Stockwell

doi:10.1021/ml500044g

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

ACS Med Chem Lett. 2014 Apr 25;5(7):754-9. doi: 10.1021/ml500044g. eCollection 2014 Jul 10.

Authors

Alexandra M Cantley¹, Matthew Welsch¹, Alberto Ambesi-Impiombato², Marta Sanchez-Martin², Mi-Yeon Kim², Andras Bauer¹, Adolfo Ferrando³, Brent R Stockwell⁴

Affiliations

¹ Department of Biological Sciences, Department of Chemistry, and Howard Hughes Medical Institute, Columbia University , 1208 Northwest Corner Building, 12th Floor, 550 West 120th Street, MC 4846, New York, New York 10027 United States.
² Department of Systems Biology, Columbia University Medical Center , and Institute for Cancer Genetics, Columbia University , New York, New York 10032 United States.
³ Department of Systems Biology, Columbia University Medical Center , and Institute for Cancer Genetics, Columbia University , New York, New York 10032 United States ; Department of Pathology and Department of Pediatrics, Columbia University , New York, New York 10032, United States ; Department of Pathology and Department of Pediatrics, Columbia University , New York, New York 10032, United States.
⁴ Department of Biological Sciences, Department of Chemistry, and Howard Hughes Medical Institute, Columbia University , 1208 Northwest Corner Building, 12th Floor, 550 West 120th Street, MC 4846, New York, New York 10027 United States ; Department of Biological Sciences, Department of Chemistry, and Howard Hughes Medical Institute, Columbia University , 1208 Northwest Corner Building, 12th Floor, 550 West 120th Street, MC 4846, New York, New York 10027 United States ; Department of Biological Sciences, Department of Chemistry, and Howard Hughes Medical Institute, Columbia University , 1208 Northwest Corner Building, 12th Floor, 550 West 120th Street, MC 4846, New York, New York 10027 United States ; Department of Systems Biology, Columbia University Medical Center , and Institute for Cancer Genetics, Columbia University , New York, New York 10032 United States.

Abstract

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.

Keywords: NOTCH1; T-cell acute lymphoblastic leukemia; dexamethasone; glucocorticoid resistance.

Abstract

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