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Electrophile Determines Cellular Phenotypes among XPO1-Targeting Small Molecules. | LitMetric

AI Article Synopsis

  • Covalent drug discovery is experiencing a resurgence with many small molecules recently approved by the FDA, particularly those targeting exportin-1 (XPO1) at a specific cysteine site (Cys528).
  • An example is selinexor, an anticancer drug approved in 2019, which represents a class of drugs known as selective inhibitors of nuclear export (SINEs).
  • The study highlights how variations in the structure of the electrophilic part of these molecules can switch their pharmacological effects, showcasing the importance of this functionality in drug development targeting XPO1.

Article Abstract

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.

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Source
http://dx.doi.org/10.1021/acs.jmedchem.4c00754DOI Listing

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