Syntheses and evaluation of new Quinoline derivatives for inhibition of hnRNP K in regulating oncogene c-myc transcription

• Published in: Bioorganic chemistry 2019-04, Vol.85, p.1-17
• Main Authors: Shu, Bing, Zeng, Ping, Kang, Shuangshuang, Li, Peng-Hui, Hu, Dexuan, Kuang, Guotao, Cao, Jiaojiao, Li, Xiaoya, Zhang, Meiling, An, Lin-Kun, Huang, Zhi-Shu, Li, Ding
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - metabolism; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; c-myc; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Female; Heterogeneous-Nuclear Ribonucleoprotein K - antagonists & inhibitors; Heterogeneous-Nuclear Ribonucleoprotein K - metabolism; hnRNP K; Humans; i-motif; Mice, Inbred BALB C; Mice, Nude; Molecular Docking Simulation; Protein Binding; Proto-Oncogene Proteins c-myc - genetics; Quinoline; Quinolines - chemical synthesis; Quinolines - metabolism; Quinolines - therapeutic use; Structure-Activity Relationship; Transcription, Genetic - drug effects; Xenograft Model Antitumor Assays
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2018.12.020

A new series of Quinoline derivatives were synthesized for specific binding with hnRNP K. Subsequent evaluation showed that compound 25 could bind to hnRNP K and disrupt its activity of unfolding c-myc oncogene promoter i-motif. This down-regulated c-myc transcription and expression, resulting in tumor cells apoptosis. [Display omitted] •hnRNP K can up-regulate oncogene transcription and is overexpressed in human cancers.•We synthesized various Quinoline derivatives and evaluated their affinity for hnRNP K.•25 could bind tightly to hnRNP K and disrupt its interaction with c-myc promoter DNA.•25 down-regulated c-myc transcription, which provided an oncogene regulation strategy.•25 selectively inhibited cancer cells growth in a Hela xenograft tumor model. Aberrant overexpression of heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a key feature in oncogenesis and progression of many human cancers. hnRNP K has been found to be a transcriptional activator to up-regulate c-myc gene transcription, a critical proto-oncogene for regulation of cell growth and differentiation. Therefore, down-regulation of c-myc transcription by inhibiting hnRNP K through disrupting its binding to c-myc gene promoter is a potential approach for cancer therapy. In the present study, we synthesized and screened a series of Quinoline derivatives and evaluated their binding affinity for hnRNP K. Among these derivatives, (E)-1-(4-methoxyphenyl)-3-(4-morpholino-6-nitroquinolin-2-yl)prop-2-en-1-one (compound 25) was determined to be the first-reported hnRNP K binding ligand with its KD values of 4.6 and 2.6 μM measured with SPR and MST, respectively. Subsequent evaluation showed that the binding of compound 25 to hnRNP K could disrupt its unfolding of c-myc promoter i-motif, resulting in down-regulation of c-myc transcription. Compound 25 showed a selective anti-proliferative effect on human cancer cell lines with IC50 values ranged from 1.36 to 3.59 μM. Compound 25 exhibited good tumor growth inhibition in a Hela xenograft tumor model, which might be related to its binding with hnRNP K. These findings illustrated that inhibition of DNA-binding protein hnRNP K by compound 25 could be a new and selective strategy of regulating oncogene transcription instead of targeting promoter DNA secondary structures such as G-quadruplexes or i-motifs.