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JOURNAL OF CHEMICAL RESEARCH · 2015 · IF 0.633

An Efficient Synthesis of Ceritinib (LDK378) Using a Sandmeyer Reaction

Haidong Liu,Yuan Li,Dongdong Wang,Yu Qin,Min Ji

A convenient route for the synthesis of Novartis's second-generation anaplastic lymphoma kinase inhibitor Ceritinib (LDK378) involving starting materials that are commercially available has been achieved. The procedure employed mild reaction conditions and avoided the use of expensive reagents compared to the original synthetic route reported by Novartis. More importantly, gram scale synthesis was accomplished and this protocol could be valid in drug discovery synthesis.

研究领域: 药物化学 · 有机合成 · 肿瘤学

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CELL BIOLOGY AND TOXICOLOGY · 2024 ·Vol. 40 ·期 1 ·1-25 · IF 5.3

Rutin attenuates ensartinib-induced hepatotoxicity by non-transcriptional regulation of TXNIP

Wu Wentong,Li Jinjin,Yin Yiming,Zhou Yourong,Huang Xiangliang,Cao Yashi,Chen Xueqin,Zhou Yunfang,Du Jiangxia,Xu Zhifei,Yang Bo,He Qiaojun,Yang Xiaochun,Hu Yuhuai,Yan Hao,Luo Peihua

Ensartinib, an approved ALK inhibitor, is used as a first-line therapy for advanced ALK-positive non-small cell lung cancer in China. However, the hepatotoxicity of ensartinib seriously limits its clinical application and the regulatory mechanism is still elusive. Here, through transcriptome analysis we found that transcriptional activation of TXNIP was the main cause of ensartinib-induced liver dysfunction. A high TXNIP level and abnormal TXNIP translocation severely impaired hepatic function via mitochondrial dysfunction and hepatocyte apoptosis, and TXNIP deficiency attenuated hepatocyte apoptosis under ensartinib treatment. The increase in TXNIP induced by ensartinib is related to AKT inhibition and is mediated by MondoA. Through screening potential TXNIP inhibitors, we found that the natural polyphenolic flavonoid rutin, unlike most reported TXNIP inhibitors can inhibit TXNIP by binding to TXNIP and partially promoting its proteasomal degradation. Further studies showed rutin can attenuate the hepatotoxicity of ensartinib without antagonizing its antitumor effects. Accordingly, we suggest that TXNIP is the key cause of ensartinib-induced hepatotoxicity and rutin is a potential clinically safe and feasible therapeutic strategy for TXNIP intervention. Graphical Abstract

CAS / MDL: 76-03-9

研究领域: 肿瘤学 · 药理学 · 分子生物学 · 细胞生物学

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An Efficient Synthesis of Ceritinib (LDK378) Using a Sandmeyer Reaction

Rutin attenuates ensartinib-induced hepatotoxicity by non-transcriptional regulation of TXNIP