Structure optimization, synthesis, and biological evaluation of 6-(2-amino-1H-benzo[d]imidazole-6-yl)-quinazolin-4(3H)-one derivatives as potential multi-targeted anticancer agents via Aurora A/ PI3K/BRD4 inhibition

Yanhua Fan; Fang Luo; Mingzhi Su; Qing Li; Ting Zhong; Liang Xiong; Mei Li; Meitao Yuan; Daoping Wang

doi:10.1016/j.bioorg.2023.106352

Structure optimization, synthesis, and biological evaluation of 6-(2-amino-1H-benzo[d]imidazole-6-yl)-quinazolin-4(3H)-one derivatives as potential multi-targeted anticancer agents via Aurora A/ PI3K/BRD4 inhibition

Bioorg Chem. 2023 Mar:132:106352. doi: 10.1016/j.bioorg.2023.106352. Epub 2023 Jan 18.

Authors

Yanhua Fan¹, Fang Luo², Mingzhi Su¹, Qing Li¹, Ting Zhong¹, Liang Xiong¹, Mei Li¹, Meitao Yuan¹, Daoping Wang¹

Affiliations

¹ State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, China.
² State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, China. Electronic address: 17810259289@163.com.

PMID: 36682147
DOI: 10.1016/j.bioorg.2023.106352

Abstract

Aurora A (Aurora kinase A), a critical regulator of cell mitosis, is frequently overexpressed in many malignant cancers, and has been considered as a promising drug target for cancer therapy. Likewise, Phosphatidylinositol 3-kinase alpha (PI3Kα) is also regarded as one of the most important targets in cancer therapy by mediating the cell growth and angiogenesis of various human cancers. In addition, Bromodomain-containing protein 4 (BRD4) modulates oncogene expressions of Myc, Aurora kinase and various RTKs. Recently, accumulating evidences indicated that hyperactivated or abnormally expressed Aurora A, PI3Kα or BRD4 are closely associated with drug resistance and poor prognosis of non-small cell lung cancer (NSCLC). Hence, simultaneous inhibition of Aurora A, PI3Kα, and BRD4 is expected to be a new strategy for NSCLC therapy. In this study, we performed further structure optimization of 6-(2-amino-1H-benzo[d]imidazole-6-yl)-quinazolin-4(3H) -one based on previous study to obtain a series of derivatives for discovering potential Aurora A, PI3Kα and BRD4 multi-targeted inhibitors. MTT assay showed that most of the newly synthesized compounds exhibited an evident anticancer activity against the NSCLC cells. Among them, the IC₅₀ values of the most potent compound 9a were 0.83, 0.26 and 1.02 μM against A549, HCC827 and H1975 cells, respectively. In addition, 9a markedly inhibited the Aurora A and PI3Kα kinase activities with IC₅₀ values of 10.19 nM and 13.12 nM. Compound 9a induced G2/M phase arrests and apoptosis of HCC827 cells by simultaneous inhibition of Aurora A/PI3K/ BRD4 signaling pathways. Collectively, our studies suggested that 9a might be a potential multi-targeted inhibitor for NSCLC therapy.

Keywords: Aurora A; BRD4; Multi-targeted inhibitor; Non-small cell lung cancer; PI3Kα; Quinazolin-4(3H)-one moiety; Structure optimization.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / chemistry
Aurora Kinase A / metabolism
Aurora Kinase A / pharmacology
Carcinoma, Non-Small-Cell Lung* / drug therapy
Cell Line, Tumor
Cell Proliferation
Drug Screening Assays, Antitumor
Humans
Imidazoles / pharmacology
Lung Neoplasms*
Molecular Structure
Nuclear Proteins / metabolism
Phosphatidylinositol 3-Kinases / metabolism
Protein Kinase Inhibitors
Structure-Activity Relationship
Transcription Factors

Substances

Phosphatidylinositol 3-Kinases
Nuclear Proteins
Protein Kinase Inhibitors
Aurora Kinase A
Transcription Factors
Antineoplastic Agents
Imidazoles
BRD4 protein, human