Electrophile Determines Cellular Phenotypes among XPO1-Targeting Small Molecules

Area of Science:

• Medicinal Chemistry
• Molecular Pharmacology
• Drug Discovery

Background:

• Covalent drug discovery is experiencing a resurgence, with FDA-approved electrophilic small molecules targeting exportin-1 (XPO1/CRM1).
• Selective inhibitors of nuclear export (SINE) like selinexor target XPO1 at cysteine 528 (Cys528).
• New XPO1 modulators, including selective inhibitors of transcriptional activation (SITAs) and XPO1 degraders, also target Cys528.

Purpose of the Study:

• To analyze structure-activity relationships of XPO1 Cys528-targeting probes.
• To investigate how electrophile modifications influence the pharmacological class of XPO1 modulators.
• To demonstrate the critical role of electrophile functionality in determining cellular effects.

Main Methods:

• Structure-activity relationship analysis across diverse chemical series.
• Synthesis and characterization of novel XPO1 Cys528-targeting small molecules.
• Cellular assays to evaluate pharmacological effects and XPO1 modulation.

Main Results:

• The electrophilic moiety is a key determinant of cellular behavior for Cys528-targeting probes.
• Minor alterations in electrophile structure can shift XPO1 modulators between different pharmacological classes.
• This study provides a unique case of electrophile-driven pharmacological diversification.

Conclusions:

• The electrophile's chemical nature is crucial for dictating the pharmacological outcome of XPO1-targeting covalent drugs.
• Fine-tuning electrophile structure offers a strategy to develop distinct classes of XPO1 modulators.
• Understanding these structure-activity relationships is vital for rational covalent drug design targeting XPO1.