发现 SZJK-0421:用于治疗血液肿瘤和实体瘤的新型强效、低毒、选择性第二代 CRM1 抑制剂

IF 6.8 1区 医学 Q1 CHEMISTRY, MEDICINAL
Hang Miao, Yanru Qin, DingLu Shao, Qinghua Chen, Yupeng Pan, Meng Lei, Ruokun Wu, Xinran Ye, Xueyuan Wang, Yongqiang Zhu
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引用次数: 0

摘要

核输出因子染色体区域维持1(CRM1)介导各种生长调节蛋白的转运,在许多血液肿瘤和实体瘤中经常过度表达。Selinexor(KPT-330)是唯一获批的CRM1抑制剂,但严重的胃肠道和中枢神经系统毒性限制了其临床应用。本手稿设计了一系列新型第二代CRM1抑制剂,其中SZJK-0421是比KPT-330更可逆的抑制剂。SZJK-0421具有良好的肝微粒体稳定性和药代动力学特性。最重要的是,SZJK-0421 减少了对胃肠道黏膜的直接损伤,SZJK-0421 在 Sprague-Dawley (SD) 大鼠中的脑浆分布比非常低(3%),避免了因血脑屏障通透性大而引起的中枢性恶心、呕吐等胃肠道反应。此外,SZJK-0421 在实体瘤和血液肿瘤的异种移植模型中均表现出很强的抗癌功效。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Discovery of SZJK-0421: A Novel Potent, Low Toxicity, Selective Second Generation of CRM1 Inhibitor for the Treatment of Both Hematological and Solid Tumors

Discovery of SZJK-0421: A Novel Potent, Low Toxicity, Selective Second Generation of CRM1 Inhibitor for the Treatment of Both Hematological and Solid Tumors
Nuclear export factor chromosome region maintenance 1 (CRM1) mediated the transport of various growth-regulatory proteins and was frequently overexpressed in many hematologic and solid tumors. Selinexor (KPT-330) was the only approved CRM1 inhibitor, but the severe gastrointestinal and central nervous system toxicities limited its clinical application. In this manuscript, a series of novel second-generation CRM1 inhibitors were designed, in which SZJK-0421 was a more reversible inhibitor than KPT-330. The treatment of various tumor cells with SZJK-0421 significantly inhibited the function of CRM1. SZJK-0421 displayed good liver microsome stabilities and pharmacokinetic properties. Most importantly, SZJK-0421 reduced the direct damage to the gastrointestinal mucosa, and the brain plasma distribution ratio of SZJK-0421 was very low in Sprague-Dawley (SD) rats (3%), which avoided gastrointestinal reactions such as central nausea and vomiting caused by large permeability of blood–brain barrier. In addition, SZJK-0421 exhibited strong anticancer efficacy in xenograft models of both solid and hematological tumors.
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来源期刊
Journal of Medicinal Chemistry
Journal of Medicinal Chemistry 医学-医药化学
CiteScore
4.00
自引率
11.00%
发文量
804
审稿时长
1.9 months
期刊介绍: The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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