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.

中文翻译：

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SZJK-0421 的发现：一种用于治疗血液瘤和实体瘤的新型有效、低毒性、选择性第二代 CRM1 抑制剂


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，并且经常在许多血液肿瘤和实体瘤中过表达。塞利尼索 （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。在本手稿中，设计了一系列新型第二代 CRM1 抑制剂，其中 SZJK-0421 是一种比 KPT-330 更具可逆性的抑制剂。用 SZJK-0421 处理各种肿瘤细胞显著抑制了 CRM1 的功能。SZJK-0421 具有良好的肝脏微粒体稳定性和药代动力学特性。最重要的是，SZJK-0421 减少了对胃肠道粘膜的直接损伤，SZJK-0421 在 Sprague-Dawley （SD） 大鼠中的脑血浆分布比非常低 （3%），避免了血脑屏障通透性大引起的中枢性恶心、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。