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

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.

Activation of orphan receptor GPR132 induces cell differentiation in acute myeloid leukemia

“…S2H ). SPI-1 and C/EBPα were two known transcription factors for up-regulating the expression of CD11b and CD14, and promoting myeloid cell differentiation [ 38 – 40 ]. We found that overexpression of GPR132 elevated the mRNA levels of SPI1 and CEBPA (Supplemental Fig.…”

Transcription Factors, R-Loops and Deubiquitinating Enzymes: Emerging Targets in Myelodysplastic Syndromes and Acute Myeloid Leukemia

“…In the case of reduced CEBPa, increasing the level/activity of this pro-differentiative TF could be a valuable option in promoting granulocytic differentiation. High-throughput screening identified small molecules selectively activating CEBPa [334] and more innovative strategies exploring short-activating RNAs (saRNAs [335]) are under development [336]. Other studies, beyond the main scope of this review, aim to restore CEBPa function by blocking the CEBPa upstream suppressor RAC1 [337] or by targeting the downstream CEBPa p30 tumor-promoting targets [338].…”

(7E)-3-(4-Methoxyphenyl)-7-[(4-methoxyphenyl)methylidene]-4,5,6,7-tetrahydro-3aH-indazole

“…The synthesis of the title compound (3) was performed according to synthesis method of styryl quinazolinones derivatives reported earlier [12,13]. A mixture of 3-(4-methoxyphenyl)-3, 3a,4,5,6,7-hexahydro-2H-indazole (115 mg, 0.5 mmol) and 4-methoxy-benzaldehyde (68 mg, 0.5 mmol) was dissolved in glacial acetic acid (10 mL) and refluxed at 120 • C for 3 h until completion (TLC monitoring).…”