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ACS chemical biology

Chemoproteomics-Enabled Covalent Ligand Screening Reveals a Thioredoxin-Caspase 3 Interaction Disruptor That Impairs Breast Cancer Pathogenicity.


PMID 28892616

Abstract

Covalent ligand discovery is a promising strategy to develop small-molecule effectors against therapeutic targets. Recent studies have shown that dichlorotriazines are promising reactive scaffolds that preferentially react with lysines. Here, we have synthesized a series of dichlorotriazine-based covalent ligands and have screened this library to reveal small molecules that impair triple-negative breast cancer cell survival. Upon identifying a lead hit from this screen KEA1-97, we used activity-based protein profiling (ABPP)-based chemoproteomic platforms to identify that this compound targets lysine 72 of thioredoxin-a site previously shown to be important in protein interactions with caspase 3 to inhibit caspase 3 activity and suppress apoptosis. We show that KEA1-97 disrupts the interaction of thioredoxin with caspase 3, activates caspases, and induces apoptosis without affecting thioredoxin activity. Moreover, KEA1-97 impairs in vivo breast tumor xenograft growth. Our study showcases how the screening of covalent ligands can be coupled with ABPP platforms to identify unique anticancer lead and target pairs.

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SML2180
KEA1-97, ≥98% (HPLC)
C15H9Cl2FN4