PUBLICATION
Discovery and Development of the Quininib Series of Ocular Drugs
- Authors
- Mahon, N., Slater, K., O'Brien, J., Alvarez, Y., Reynolds, A., Kennedy, B.
- ID
- ZDB-PUB-220129-12
- Date
- 2022
- Source
- Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics 38: 33-42 (Journal)
- Registered Authors
- Alvarez, Yolanda, Kennedy, Breandan N., Reynolds, Alison
- Keywords
- cysteinyl leukotriene receptors, ocular angiogenesis, phenotype-based drug discovery, quininib drug series, zebrafish
- MeSH Terms
-
- Angiogenesis Inhibitors/pharmacology*
- Angiogenesis Inhibitors/therapeutic use*
- Animals
- Diabetic Retinopathy/drug therapy
- Disease Models, Animal
- Drug Development/methods
- Drug Discovery/methods
- Eye Neoplasms/drug therapy
- Neovascularization, Pathologic/drug therapy
- Phenols/pharmacology*
- Phenols/therapeutic use*
- Phenotype
- Quinolines/pharmacology*
- Quinolines/therapeutic use*
- Receptors, Leukotriene/drug effects
- Retinal Diseases/drug therapy*
- Retinal Neovascularization/drug therapy
- PubMed
- 35089801 Full text @ J. Ocul. Pharmacol. Ther.
Citation
Mahon, N., Slater, K., O'Brien, J., Alvarez, Y., Reynolds, A., Kennedy, B. (2022) Discovery and Development of the Quininib Series of Ocular Drugs. Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics. 38:33-42.
Abstract
The quininib series is a novel collection of small-molecule drugs with antiangiogenic, antivascular permeability, anti-inflammatory, and antiproliferative activity. Quininib was initially identified as a drug hit during a random chemical library screen for determinants of developmental ocular angiogenesis in zebrafish. To enhance drug efficacy, novel quininib analogs were designed by applying medicinal chemistry approaches. The resulting quininib drug series has efficacy in in vitro and ex vivo models of angiogenesis utilizing human cell lines and tissues. In vivo, quininib drugs reduce pathological angiogenesis and retinal vascular permeability in rodent models. Quininib acts as a cysteinyl leukotriene (CysLT) receptor antagonist, revealing new roles of these G-protein-coupled receptors in developmental angiogenesis of the eye and unexpectedly in uveal melanoma (UM). The quininib series highlighted the potential of CysLT receptors as therapeutic targets for retinal vasculopathies (e.g., neovascular age-related macular degeneration, diabetic retinopathy, and diabetic macular edema) and ocular cancers (e.g., UM).
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping