Chemoproteomics-Enabled Covalent Ligand Screening Reveals a Thioredoxin-Caspase 3 Interaction Disruptor That Impairs Breast Cancer Pathogenicity
Open accessAbstract
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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The compound KEA1-97, identified using an ABPP-based chemoproteomic platform, targeted the lysine-72 site of thioredoxin to disrupt its PPI with caspase-3, leading to the activation of apoptosis.
“The compound KEA1-97, identified using a ABPP-based chemoproteomic platform, targeted the lysine-72 site of thioredoxin to disrupt its PPI with caspase-3, leading to the activation of apoptosis [70].”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [70]
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- Authors
- Anderson, K. E., To, M., Olzmann, J. A., & Nomura, D. K.
- Affiliations
- University of California, Berkeley (US)
- Corresponding author
- Nomura, Daniel K.
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2017-09-13
- Volume
- 12
- Issue
- 10
- Pages
- 2522-2528
- ISSN
- 1554-8929 (ISSN-L)
- 1554-8937
- PMC
- PMC6205226
- OpenAlex
- W2754208640
- Cited by
- 35
- References
- 18
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 3 · 2021: 4 · 2020: 3 · 2019: 8 · 2018: 6 · 2017: 1
- FWCI
- 2.06
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- ACS Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Novartis
- National Cancer Institute (R01 CA172667)
- Congressionally Directed Medical Research Programs (W81XWH-15-1-10050)
- American Cancer Society (RSG14-242-01-TBE)
- National Institute of General Medical Sciences (R01 GM112948)
- Novartis-Berkeley Center for Proteomics and Chemistry Technologies
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- chemoproteomics, activity-based protein profiling, thioredoxin, caspase-3, triple-negative breast cancer, apoptosis
- MeSH terms
- Animals, Antineoplastic Agents, Biphenyl Compounds, Breast Neoplasms, Female, Humans, Ligands, Male, Neoplasms, Experimental, Thioredoxins, Triazines, Molecular Structure, Mice, SCID, Proteomics, Cell Line, Tumor, Mice, Caspase 3
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