Background:

TG003 is a potent and selective inhibitor of Clk-family kinases with IC50 values of 15, 20, 200 nM and >10 μM for mClk4, 1, 2 and 3, respectively [1]. Also, TG003 is also an inhibitor of casein kinase 1 (CK1) [2].

Cdc2-like kinases (Clks) family consist of Clk1, 2, 3 and 4 and play an important role in mRNA splice site selection. Clks phosphorylate serine/arginine-rich proteins that involved in pre-mRNA processing and release them into the nucleoplasm.

TG003 is a potent and selective Clk-family kinases inhibitor. TG003 competed with ATP with Ki value of 0.01 μM on Clk1/Sty. In HeLa cytosolic S100 extract, TG003 inhibited Clk1/Sty-mediated phosphorylation of SF2/ASF, which played an important role in alternative splicing. Also, TG003 inhibited the splicing of β-globin pre-mRNA when complemented with rSF2/ASF. In HA-Clk1/Sty-overexpressing HeLa cells, TG003 (10 μM) reversibly inhibited phosphorylation of SR proteins and caused HA-Clk1/Sty localized in nuclear speckles [1].

In mice, TG003 inhibited the alteration of splicing site selection induced by Clk1/Sty and affected the alternative splicing of endogenous genes. In X. laevis embryo, TG003 (10μM) rescued the morphological abnormalities in the dorsal ectoderm and mesoderm induced by the overexpression of xClk kinase [1].

参考文献:
[1].  Muraki M, Ohkawara B, Hosoya T, et al. Manipulation of alternative splicing by a newly developed inhibitor of Clks. J Biol Chem, 2004, 279(23): 24246-24254.
[2].  Kurihara T, Sakurai E, Toyomoto M, et al. Alleviation of behavioral hypersensitivity in mouse models of inflammatory pain with two structurally different casein kinase 1 (CK1) inhibitors. Mol Pain, 2014, 10: 17.