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Molecules 2018, 23(8), 1938;

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

Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
Department of Hematology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
Department of Chemistry, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad-500 085, India
School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi-110 062, India
Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA
Division of translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Takaomi Sanda
Received: 22 June 2018 / Revised: 30 July 2018 / Accepted: 31 July 2018 / Published: 3 August 2018
(This article belongs to the Special Issue Transcription Factors as Therapeutic Targets)
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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. View Full-Text
Keywords: myeloid differentiation; CCAAT/enhancer binding protein α myeloid differentiation; CCAAT/enhancer binding protein α

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Sridhar, R.; Takei, H.; Syed, R.; Kobayashi, I.S.; Hui, L.B.; Kamal, A.; Tenen, D.G.; Kobayashi, S.S. Styryl Quinazolinones as Potential Inducers of Myeloid Differentiation via Upregulation of C/EBPα. Molecules 2018, 23, 1938.

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