Identification of a Dual Inhibitor of SRPK1 and CK2 That Attenuates Pathological Angiogenesis of Macular Degeneration in Mice.
Mol Pharmacol
; 88(2): 316-25, 2015 Aug.
Article
em En
| MEDLINE
| ID: mdl-25993998
ABSTRACT
Excessive angiogenesis contributes to numerous diseases, including cancer and blinding retinopathy. Antibodies against vascular endothelial growth factor (VEGF) have been approved and are widely used in clinical treatment. Our previous studies using SRPIN340, a small molecule inhibitor of SRPK1 (serine-arginine protein kinase 1), demonstrated that SRPK1 is a potential target for the development of antiangiogenic drugs. In this study, we solved the structure of SRPK1 bound to SRPIN340 by X-ray crystallography. Using pharmacophore docking models followed by in vitro kinase assays, we screened a large-scale chemical library, and thus identified a new inhibitor of SRPK1. This inhibitor, SRPIN803, prevented VEGF production more effectively than SRPIN340 owing to the dual inhibition of SRPK1 and CK2 (casein kinase 2). In a mouse model of age-related macular degeneration, topical administration of eye ointment containing SRPIN803 significantly inhibited choroidal neovascularization, suggesting a clinical potential of SRPIN803 as a topical ointment for ocular neovascularization. Thus SRPIN803 merits further investigation as a novel inhibitor of VEGF.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirimidinonas
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Tiadiazóis
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Proteínas Serina-Treonina Quinases
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Neovascularização de Coroide
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Caseína Quinase II
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Inibidores Enzimáticos
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Bibliotecas de Moléculas Pequenas
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Mol Pharmacol
Ano de publicação:
2015
Tipo de documento:
Article