Covalent Ligand Discovery against Druggable Hotspots Targeted by Anti-cancer Natural Products.
Cell Chem Biol
; 24(11): 1368-1376.e4, 2017 Nov 16.
Article
em En
| MEDLINE
| ID: mdl-28919038
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
/
Tipos_de_cancer
/
Outros_tipos
Base de dados:
MEDLINE
Assunto principal:
Produtos Biológicos
/
Proteína Fosfatase 2
/
Antineoplásicos
Limite:
Female
/
Humans
Idioma:
En
Revista:
Cell Chem Biol
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos