Ocular Toxicity Profile of ST-162 and ST-168 as Novel Bifunctional MEK/PI3K Inhibitors.

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.

• Authors: Andrew Smith, Mercy Pawar, Marcian E Van Dort, Stefanie Galbán, Amanda R Welton, Greg M Thurber, Brian D Ross, Cagri G Besirli
• Journal: Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics (J Ocul Pharmacol Ther) 2018 Jul/Aug Vol. 34 Issue 6 Pg. 477-485 ISSN: 1557-7732 [Electronic] United States
• PMID: 29708810 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• MAP Kinase Kinase Kinases

Topics

• Animals
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cells, Cultured
• Eye (drug effects)
• Humans
• Intravitreal Injections
• MAP Kinase Kinase Kinases (antagonists & inhibitors, metabolism)
• Male
• Mice
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacology)
• Rabbits
• Visual Acuity (drug effects)