Identification of a Dual Inhibitor of SRPK1 and CK2 That Attenuates Pathological Angiogenesis of Macular Degeneration in Mice

Satoshi Morooka; Mitsuteru Hoshina; Isao Kii; Takayoshi Okabe; Hirotatsu Kojima; Naoko Inoue; Yukiko Okuno; Masatsugu Denawa; Suguru Yoshida; Junichi Fukuhara; Kensuke Ninomiya; Teikichi Ikura; Toshio Furuya; Tetsuo Nagano; Kousuke Noda; Susumu Ishida; Takamitsu Hosoya; Nobutoshi Ito; Nagahisa Yoshimura; Masatoshi Hagiwara

doi:10.1124/mol.114.097345

Identification of a Dual Inhibitor of SRPK1 and CK2 That Attenuates Pathological Angiogenesis of Macular Degeneration in Mice

Mol Pharmacol. 2015 Aug;88(2):316-25. doi: 10.1124/mol.114.097345. Epub 2015 May 20.

Authors

Satoshi Morooka¹, Mitsuteru Hoshina¹, Isao Kii¹, Takayoshi Okabe¹, Hirotatsu Kojima¹, Naoko Inoue¹, Yukiko Okuno¹, Masatsugu Denawa¹, Suguru Yoshida¹, Junichi Fukuhara¹, Kensuke Ninomiya¹, Teikichi Ikura¹, Toshio Furuya¹, Tetsuo Nagano¹, Kousuke Noda¹, Susumu Ishida¹, Takamitsu Hosoya¹, Nobutoshi Ito¹, Nagahisa Yoshimura¹, Masatoshi Hagiwara²

Affiliations

¹ Department of Ophthalmology and Visual Sciences (S.M., N.Y.), Department of Anatomy and Developmental Biology (S.M., I.K., Ke.N., Ma.H.), and Medical Research Support Center (Y.O., M.D.), Graduate School of Medicine, Kyoto University, Kyoto, Japan; Laboratory of Structural Biology, Medical Research Institute (Mi.H., No.I., T.I.), and Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering (S.Y., T.H.), Tokyo Medical and Dental University, Tokyo, Japan; Open Innovation Center for Drug Discovery, The University of Tokyo, Tokyo, Japan (T.O., H.K., T.N.); PharmaDesign, Inc., Tokyo, Japan (Na.I., T.F.); and Department of Ophthalmology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan (J.F., Ko.N., S.I.).
² Department of Ophthalmology and Visual Sciences (S.M., N.Y.), Department of Anatomy and Developmental Biology (S.M., I.K., Ke.N., Ma.H.), and Medical Research Support Center (Y.O., M.D.), Graduate School of Medicine, Kyoto University, Kyoto, Japan; Laboratory of Structural Biology, Medical Research Institute (Mi.H., No.I., T.I.), and Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering (S.Y., T.H.), Tokyo Medical and Dental University, Tokyo, Japan; Open Innovation Center for Drug Discovery, The University of Tokyo, Tokyo, Japan (T.O., H.K., T.N.); PharmaDesign, Inc., Tokyo, Japan (Na.I., T.F.); and Department of Ophthalmology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan (J.F., Ko.N., S.I.) hagiwara.masatoshi.8c@kyoto-u.ac.jp.

PMID: 25993998
DOI: 10.1124/mol.114.097345

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Topical
Animals
Casein Kinase II / antagonists & inhibitors*
Cell Line
Choroidal Neovascularization / drug therapy*
Crystallography, X-Ray
Disease Models, Animal
Enzyme Inhibitors / administration & dosage*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Humans
Macular Degeneration / drug therapy
Macular Degeneration / pathology
Mice
Models, Molecular
Molecular Docking Simulation
Niacinamide / analogs & derivatives
Niacinamide / chemistry
Piperidines / chemistry
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / chemistry*
Protein Serine-Threonine Kinases / metabolism
Pyrimidinones / administration & dosage*
Pyrimidinones / chemistry
Pyrimidinones / pharmacology
Small Molecule Libraries / administration & dosage*
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology
Structure-Activity Relationship
Thiadiazoles / administration & dosage*
Thiadiazoles / chemistry
Thiadiazoles / pharmacology

Substances

Enzyme Inhibitors
Piperidines
Pyrimidinones
SRPIN340
SRPIN803
Small Molecule Libraries
Thiadiazoles
Niacinamide
SRPK1 protein, human
Casein Kinase II
Protein Serine-Threonine Kinases