title: Identification of a Dual Inhibitor of SRPK1 and CK2 That Attenuates Pathological Angiogenesis of Macular Degeneration in Mice.
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.
authors.affiliation: 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.).
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morooka
authors.affiliation: 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.).
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Hoshina
authors.affiliation: 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.).
authors.forename: Isao
authors.initials: I
authors.lastname: Kii
authors.affiliation: 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.).
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Okabe
authors.affiliation: 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.).
authors.forename: Hirotatsu
authors.initials: H
authors.lastname: Kojima
authors.affiliation: 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.).
authors.forename: Naoko
authors.initials: N
authors.lastname: Inoue
authors.affiliation: 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.).
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Okuno
authors.affiliation: 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.).
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Denawa
authors.affiliation: 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.).
authors.forename: Suguru
authors.initials: S
authors.lastname: Yoshida
authors.affiliation: 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.).
authors.forename: Junichi
authors.initials: J
authors.lastname: Fukuhara
authors.affiliation: 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.).
authors.forename: Kensuke
authors.initials: K
authors.lastname: Ninomiya
authors.affiliation: 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.).
authors.forename: Teikichi
authors.initials: T
authors.lastname: Ikura
authors.affiliation: 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.).
authors.forename: Toshio
authors.initials: T
authors.lastname: Furuya
authors.affiliation: 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.).
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nagano
authors.affiliation: 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.).
authors.forename: Kousuke
authors.initials: K
authors.lastname: Noda
authors.affiliation: 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.).
authors.forename: Susumu
authors.initials: S
authors.lastname: Ishida
authors.affiliation: 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.).
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Hosoya
authors.affiliation: 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.).
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Ito
authors.affiliation: 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.).
authors.forename: Nagahisa
authors.initials: N
authors.lastname: Yoshimura
authors.affiliation: 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.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hagiwara
mesh_terms: D000287:Administration, Topical; D000818:Animals; D047390:Casein Kinase II / Q000037:antagonists & inhibitors*; D002460:Cell Line; D020256:Choroidal Neovascularization / Q000188:drug therapy*; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008268:Macular Degeneration / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009536:Niacinamide / Q000031:analogs & derivatives / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D011744:Pyrimidinones / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D010880:Piperidines; D011744:Pyrimidinones; C584061:SRPIN340; C000601054:SRPIN803; D054852:Small Molecule Libraries; D013830:Thiadiazoles; D009536:Niacinamide; C087728:SRPK1 protein, human; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases