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 <b>SZJK-0421</b> was a more reversible inhibitor than KPT-330. The treatment of various tumor cells with <b>SZJK-0421</b> significantly inhibited the function of CRM1. <b>SZJK-0421</b> displayed good liver microsome stabilities and pharmacokinetic properties. Most importantly, <b>SZJK-0421</b> reduced the direct damage to the gastrointestinal mucosa, and the brain plasma distribution ratio of <b>SZJK-0421</b> 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, <b>SZJK-0421</b> exhibited strong anticancer efficacy in xenograft models of both solid and hematological tumors.