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Cell Chem Biol. 2017 Nov 16;24(11):1368-1376.e4. doi: 10.1016/j.chembiol.2017.08.013. Epub 2017 Sep 14.

Covalent Ligand Discovery against Druggable Hotspots Targeted by Anti-cancer Natural Products.

Author information

1
Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, 127 Morgan Hall, Berkeley, CA 94720, USA.
2
Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, 127 Morgan Hall, Berkeley, CA 94720, USA. Electronic address: dnomura@berkeley.edu.

Abstract

Many natural products that show therapeutic activities are often difficult to synthesize or isolate and have unknown targets, hindering their development as drugs. Identifying druggable hotspots targeted by covalently acting anti-cancer natural products can enable pharmacological interrogation of these sites with more synthetically tractable compounds. Here, we used chemoproteomic platforms to discover that the anti-cancer natural product withaferin A targets C377 on the regulatory subunit PPP2R1A of the tumor-suppressor protein phosphatase 2A (PP2A) complex leading to activation of PP2A activity, inactivation of AKT, and impaired breast cancer cell proliferation. We developed a more synthetically tractable cysteine-reactive covalent ligand, JNS 1-40, that selectively targets C377 of PPP2R1A to impair breast cancer signaling, proliferation, and in vivo tumor growth. Our study highlights the utility of using chemoproteomics to map druggable hotspots targeted by complex natural products and subsequently interrogating these sites with more synthetically tractable covalent ligands for cancer therapy.

KEYWORDS:

PP2A; PPP2R1A; activity-based protein profiling; chemical biology; chemoproteomics; covalent ligand discovery; cysteine; protein phosphatase 2A; withaferin

PMID:
28919038
PMCID:
PMC5693770
DOI:
10.1016/j.chembiol.2017.08.013
[Indexed for MEDLINE]
Free PMC Article

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