Ocular Toxicity Profile of ST-162 and ST-168 as Novel Bifunctional MEK/PI3K Inhibitors.
J Ocul Pharmacol Ther
; 34(6): 477-485, 2018.
Article
in En
| MEDLINE
| ID: mdl-29708810
ABSTRACT
PURPOSE:
ST-162 and ST-168 are small-molecule bifunctional inhibitors of MEK and PI3K signaling pathways that are being developed as novel antitumor agents. Previous small-molecule and biologic MEK inhibitors demonstrated ocular toxicity events that were dose limiting in clinical studies. We evaluated in vitro and in vivo ocular toxicity profiles of ST-162 and ST-168.METHODS:
Photoreceptor cell line 661W and adult retinal pigment epithelium cell line ARPE-19 were treated with increasing concentrations of bifunctional inhibitors. Western blots, cell viability, and caspase activity assays were performed to evaluate MEK and PI3K inhibition and dose-dependent in vitro toxicity, and compared with monotherapy. In vivo toxicity profile was assessed by intravitreal injection of ST-162 and ST-168 in Dutch-Belted rabbits, followed by ocular examination and histological analysis of enucleated eyes.RESULTS:
Retinal cell lines treated with ST-162 or ST-168 exhibited dose-dependent inhibition of MEK and PI3K signaling. Compared with inhibition by monotherapies and their combinations, bifunctional inhibitors demonstrated reduced cell death and caspase activity. In vivo, both bifunctional inhibitors exhibited a more favorable toxicity profile when compared with MEK inhibitor PD0325901.CONCLUSIONS:
Novel MEK and PI3K bifunctional inhibitors ST-162 and ST-168 demonstrate favorable in vitro and in vivo ocular toxicity profiles, supporting their further development as potential therapeutic agents targeting multiple aggressive tumors.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Visual Acuity
/
MAP Kinase Kinase Kinases
/
Protein Kinase Inhibitors
/
Eye
/
Phosphoinositide-3 Kinase Inhibitors
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
J Ocul Pharmacol Ther
Journal subject:
FARMACOLOGIA
/
OFTALMOLOGIA
/
TERAPEUTICA
Year:
2018
Document type:
Article