Electrophile Determines Cellular Phenotypes among XPO1-Targeting Small Molecules

Covalent drug discovery has experienced a renaissance,
with numerous
electrophilic small molecules recently gaining FDA approval. Many
structurally diverse electrophilic small molecules target exportin-1
(XPO1/CRM1) at cysteine 528, including the selective inhibitor of
nuclear export (SINE) selinexor, which was FDA-approved as an anticancer
agent in 2019. Emerging evidence supports additional pharmacological
classes of XPO1 modulators targeting Cys528, including the selective
inhibitors of transcriptional activation (SITAs) and probes that induce
rapid degradation of XPO1. Here, we analyzed structure–activity
relationships across multiple structural series of XPO1 Cys528-targeting
probes. We observe that the electrophilic moiety of Cys528-targeting
small molecules plays a decisive role in the cellular behavior observed,
with subtle changes in electrophile structure being sufficient to
convert XPO1-targeting probes to different pharmacological classes.
This investigation represents a unique case study in which the electrophile
functionality used to target a specific cysteine determines the pharmacological
effect among diverse XPO1-targeting small molecules.