Discovery of Aminoratjadone Derivatives as Potent Noncovalent CRM1 Inhibitors

• Cancer cells frequently utilize elevated nuclear exportto escapetumor suppression and gain proliferative advantage. Chromosome RegionMaintenance 1 (CRM1/XPO1) mediates macromolecule nuclear export andplays an important role in tumorigenesis and progression. The clinicalapproval of its covalent inhibitor KPT-330 (Selinexor) validates thefeasibility of targeting CRM1 to treat cancers. Here, we synthesizedfour aminoratjadone derivatives and found that two of them, KL1 and KL2, are noncovalent CRM1 inhibitors.The two compounds underwent spontaneous hydrolysis in aqueous buffers,and the resulting products were more active against CRM1. High-resolutioncrystal structures revealed the CRM1-binding mode of these compoundsand explained the observed structure-activity relationships.In cells, KL1 and KL2 localized CRM1 inthe nuclear periphery and led to depletion of nuclear CRM1, therebyinhibiting the nuclear export and growth of colorectal cancer cellsat submicromolar concentrations. This work lays the foundation forfurther development of aminoratjadone-based noncovalent CRM1 inhibitors.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)

Keyword

nuclear export

leptomycin b

covalent

degradation

design

cells

Pharmacology & Pharmacy

Publication and Content Type

ref (subject category)

art (subject category)