2. Academic Validation
  3. Styryl Quinazolinones as Potential Inducers of Myeloid Differentiation via Upregulation of C/EBPα

Styryl Quinazolinones as Potential Inducers of Myeloid Differentiation via Upregulation of C/EBPα

  • Molecules. 2018 Aug 3;23(8):1938. doi: 10.3390/molecules23081938.
Radhakrishnan Sridhar 1,  Hisashi Takei 2 3,  Riyaz Syed 4 5,  Ikei S Kobayashi 6,  Liu Bee Hui 7,  Ahmed Kamal 8 9,  Daniel G Tenen 10 11,  Susumu S Kobayashi 12 13 14
Affiliations

Affiliations

  • 1 Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore. [email protected].
  • 2 Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. [email protected].
  • 3 Department of Hematology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan. [email protected].
  • 4 Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India. [email protected].
  • 5 Department of Chemistry, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad-500 085, India. [email protected].
  • 6 Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. [email protected].
  • 7 Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore. [email protected].
  • 8 Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India. [email protected].
  • 9 School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi-110 062, India. [email protected].
  • 10 Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore. [email protected].
  • 11 Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA. [email protected].
  • 12 Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. [email protected].
  • 13 Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA. [email protected].
  • 14 Division of translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan. [email protected].
PMID: 30081475 DOI: 10.3390/molecules23081938
Abstract

The CCAAT enhancer-binding protein α (C/EBPα) plays an important role in myeloid cell differentiation and in the enhancement of C/EBPα expression/activity, which can lead to granulocytic differentiation in acute myeloid leukemia (AML) cells. We found that styryl quinazolinones induce upregulation of C/EBPα expression, and thereby induce myeloid differentiation in human myeloid leukemia cell lines. We screened a series of active styryl quinazolinones and evaluated the structure⁻activity relationship (SAR) of these small molecules in inducing C/EBPα expression-thereby prompting the leukemic cells to differentiate. We observed that compound 78 causes differentiation at 3 μM concentration, while 1 induces differentiation at 10 μM concentration. We also observed an increase in the expression of neutrophil differentiation marker CD11b upon treatment with 78. Both the C/EBPα and C/EBPε levels were found to be upregulated by treatment with 78. These SAR findings are inspiration to develop further modified styryl quinazolinones, in the path of this novel differentiation therapy, which can contribute to the care of patients with AML.

Keywords

CCAAT/enhancer binding protein α; myeloid differentiation.

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