Discovery of\nSZJK-0421:\nA Novel Potent, Low Toxicity,\nSelective Second Generation of CRM1 Inhibitor for the Treatment of\nBoth Hematological and Solid Tumors

Nuclear\nexport factor chromosome region maintenance 1 (CRM1) mediated\nthe transport of various growth-regulatory proteins and was frequently\noverexpressed in many hematologic and solid tumors. Selinexor (KPT-330)\nwas the only approved CRM1 inhibitor, but the severe gastrointestinal\nand central nervous system toxicities limited its clinical application.\nIn this manuscript, a series of novel second-generation CRM1 inhibitors\nwere designed, in which <b>SZJK-0421</b> was a more reversible\ninhibitor 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\nproperties. Most importantly, <b>SZJK-0421</b> reduced the direct\ndamage to the gastrointestinal mucosa, and the brain plasma distribution\nratio of <b>SZJK-0421</b> was very low in Sprague-Dawley (SD)\nrats (3%), which avoided gastrointestinal reactions such as central\nnausea and vomiting caused by large permeability of blood–brain\nbarrier. In addition, <b>SZJK-0421</b> exhibited strong anticancer\nefficacy in xenograft models of both solid and hematological tumors.