SRPIN803 can prevent VEGF production owing to the dual inhibition of SRPK1 and CK2. SRPKs are a critical enzyme family that regulates splicing activity in the cell. Serine-arginine protein kinase 1 (SRPK1) is the prototype of the SRPK family, which also includes the two homologous SRPK2 and SRPK3 proteins. SRPKs can translocate into the nucleus of cells under several conditions, such as during the G2/M phase of the cell cycle, after osmotic stress, or as a consequence of activation of the epidermal growth factor (EGF) signal transduction pathway.
Casein Kinases (CKs), a group of ubiquitous Ser/Thr kinases, regulate a wide range of cellular functions in eukaryotes. Two casein kinases, casein kinase-1 (CK-1) and casein kinase-2 (CK-2). CK1 kinases exist in at least seven isoforms (α, β, γ1-3, δ, and ɛ) in mammals and CK1 kinases phosphorylate various substrates to play vital roles in diverse physiological processes such as DNA repair, cell cycle progression, cytokinesis, differentiation, and apoptosis. Casein kinase 2 (CK2) is a highly pleiotropic serine-threonine kinase, which catalyzed the phosphorylation of more than 300 proteins that are implicated in the regulation of many cellular functions, such as signal transduction, transcriptional control, apoptosis, and the cell cycle.
SRPIN803 is a potent CK2 and SRPK1 dual inhibitor.
SRPIN803 inhibits the activity of SRPK1 toward LBRNt (62-92), while the c(RGDyK)-conjugated compounds completely abolish its inhibitory activity. Moreover, SRPIN803 has slight cytostatic activity against Hcc827, PC3, and U87. Importantly, SRPIN803 has the potential for the research of age-related macular degeneration. SRPIN803 (topical administration of eye ointment) significantly inhibits choroidal neovascularization in a mouse model of age-related macular degeneration. Besides, SRPIN803 exhibits antiangiogenic activity. For example, SRPIN803 inhibits zebrafish angiogenesis at a concentration of 100 μM. Meanwhile, SRPIN803 blocks angiogenesis in the developing embryo at the one-cell stage of zebrafish.
All in all, SRPIN803 is a potent CK2 and SRPK1 dual inhibitor that exhibits antiangiogenic activity.
References:
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[2] Borgo C, et, al. Signal Transduct Target Ther. 2021 May 17;6(1):183.
[3] Vedove AD, et, al. Eur J Med Chem. 2020 Jun 1;195:112267.