Design and synthesis of emodin derivatives as novel inhibitors of ATP-citrate lyase.
Eur J Med Chem
; 126: 920-928, 2017 Jan 27.
Article
in En
| MEDLINE
| ID: mdl-27997879
ABSTRACT
Aberrant cellular metabolism drives cancer proliferation and metastasis. ATP citrate lyase (ACL) plays a critical role in generating cytosolic acetyl CoA, a key building block for de novo fatty acid and cholesterol biosynthesis. ACL is overexpressed in cancer cells, and siRNA knockdown of ACL limits cancer cell proliferation and reduces cancer stemness. We characterized a new class of ACL inhibitors bearing the key structural feature of the natural product emodin. Structure-activity relationship (SAR) study led to the identification of 1d as a potent lead that demonstrated dose-dependent inhibition of proliferation and cancer stemness of the A549 lung cancer cell line. Computational modeling indicates this class of inhibitors occupies an allosteric binding site and blocks the entrance of the substrate citrate to its binding site.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
ATP Citrate (pro-S)-Lyase
/
Drug Design
/
Emodin
/
Enzyme Inhibitors
Limits:
Humans
Language:
En
Journal:
Eur J Med Chem
Year:
2017
Document type:
Article
Affiliation country:
United States