TY - JOUR T1 - Identification of a Dual Inhibitor of SRPK1 and CK2 That Attenuates Pathological Angiogenesis of Macular Degeneration in Mice JF - Molecular Pharmacology JO - Mol Pharmacol SP - 316 LP - 325 DO - 10.1124/mol.114.097345 VL - 88 IS - 2 AU - Satoshi Morooka AU - Mitsuteru Hoshina AU - Isao Kii AU - Takayoshi Okabe AU - Hirotatsu Kojima AU - Naoko Inoue AU - Yukiko Okuno AU - Masatsugu Denawa AU - Suguru Yoshida AU - Junichi Fukuhara AU - Kensuke Ninomiya AU - Teikichi Ikura AU - Toshio Furuya AU - Tetsuo Nagano AU - Kousuke Noda AU - Susumu Ishida AU - Takamitsu Hosoya AU - Nobutoshi Ito AU - Nagahisa Yoshimura AU - Masatoshi Hagiwara Y1 - 2015/08/01 UR - http://molpharm.aspetjournals.org/content/88/2/316.abstract N2 - 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. ER -