2. Academic Validation
  3. Small Molecule that Reverses Dexamethasone Resistance in T-cell Acute Lymphoblastic Leukemia (T-ALL)

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.
Alexandra M Cantley 1,  Matthew Welsch 1,  Alberto Ambesi-Impiombato 2,  Marta Sanchez-Martin 2,  Mi-Yeon Kim 2,  Andras Bauer 1,  Adolfo Ferrando 3,  Brent R Stockwell 4
Affiliations

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.
PMID: 25050160 DOI: 10.1021/ml500044g
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-112255
    Dexamethasone Resistance Reverser