Discovery of novel VEGFR-2-PROTAC degraders based on the localization of lysine residues via recruiting VHL for the treatment of gastric cancer.
Eur J Med Chem
; 244: 114821, 2022 Dec 15.
Article
in En
| MEDLINE
| ID: mdl-36242985
ABSTRACT
VEGFR-2 is an attractive therapeutic target for antitumor drug research by blocking tumor angiogenesis and PROTAC provides a new technology for targeted protein knockout. Herein, a library of novel VEGFR-2-PROTAC degraders were rationally designed and synthesized based on the Lys residue region on the surface of VEGFR-2 protein using protein structure-based drug design strategy. Among them, P7 exhibited preferable antitumor activity against HGC-27 cells and less toxic to human normal HUVEC, HEK293T and GES-1 cells in vitro, as well as the potent degradation activity of VEGFR-2 protein in HGC-27 cells (DC50 0.084 ± 0.04 µM, Dmax 73.7%) and HUVEC cells (DC50 0.51 ± 0.10 µM, Dmax 76.6%). Additionally, P7 degraded VEGFR-2 protein by the formation of ternary complex and the ubiquitin proteasome pathway in HGC-27 cells. Furthermore, P7 shortened the half-life of VEGFR-2 protein synthesis and had no inhibitory effect on the expression of VEGFR-2 mRNA in HGC-27 cells. Moreover, P7 inhibited the colony formation, migration and invasion of HGC-27 cells in a time- and dose-dependent manner, and meanwhile induced G2/M phase cycle arrest and apoptosis. All the results demonstrated that P7 could be as a promising VEGFR-2-PROTAC degrader for gastric cancer therapy.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Stomach Neoplasms
/
Antineoplastic Agents
Limits:
Humans
Language:
En
Journal:
Eur J Med Chem
Year:
2022
Document type:
Article
Affiliation country:
China