2. Academic Validation
  3. A Cell-Based High-Throughput Screening for Inducers of Myeloid Differentiation

A Cell-Based High-Throughput Screening for Inducers of Myeloid Differentiation

  • J Biomol Screen. 2015 Oct;20(9):1150-9. doi: 10.1177/1087057115592220.
Hanna S Radomska 1,  Finith Jernigan 2,  Sohei Nakayama 3,  Susan E Jorge 3,  Lijun Sun 2,  Daniel G Tenen 4,  Susumu S Kobayashi 5
Affiliations

Affiliations

  • 1 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, OH, USA.
  • 2 Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • 3 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • 4 Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA Cancer Science Institute, National University of Singapore, Singapore.
  • 5 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA skobayas@bidmc.harvard.edu.
PMID: 26109609 DOI: 10.1177/1087057115592220
Abstract

Recent progress of genetic studies has dramatically unveiled pathogenesis of acute myeloid leukemia (AML). However, overall survival of AML still remains unsatisfactory, and development of novel therapeutics is required. CCAAT/enhancer binding protein α (C/EBPα) is one of the crucial transcription factors that induce granulocytic differentiation, and its activity is perturbed in human myeloid leukemias. As its reexpression can induce differentiation and subsequent Apoptosis of leukemic cells in vitro, we hypothesized that chemical compounds that restore C/EBPα expression and/or activity would lead to myeloid differentiation of leukemic cells. Using a cell-based high-throughput screening, we identified 2-[(E)-2-(3,4-dihydroxyphenyl)vinyl]-3-(2-methoxyphenyl)-4(3H)-quinazolinone as a potent inducer of C/EBPα and myeloid differentiation. Leukemia cell lines and primary blast cells isolated from human patients with AML treated with ICCB280 demonstrated evidence of morphological and functional differentiation, as well as massive Apoptosis. We performed conformational analyses of the high-throughput screening hit compounds to postulate the spatial requirements for high potency. Our results warrant a development of novel differentiation therapies and significantly affect care of patients with AML with unfavorable prognosis in the near future.

Keywords

2-[(E)-2-(3,4-dihydroxyphenyl)vinyl]-3-(2-methoxyphenyl)-4(3H)-quinazolinone; CCAAT/enhancer binding protein α (C/EBPα); acute myeloid leukemia; differentiation.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-134333
    99.43%, C/EBPα Inducer