TG003 (719277-26-6) is a potent, ATP-competitive inhibitor of Clk-family kinases (IC50‘s = 15, 20 and 200 nM for mClk4, 1 and 2 respectively and >10 μM for mClk3)1. Also inhibits DYRK1A/B (IC50‘s = 24 and 34 nM respectively)2. Suppresses serine/arginine-rich protein phosphorylation, dissociation of nuclear speckles and Clk1/Sty-dependent alternative splicing in mammalian cells1. TG003 affects the regulation of alternative splicing by phosphorylation of SR protein both in vitro and in vivo. Promotes skipping of exon 31 in the endogenous dystrophin gene3. TG003 increases levels of Clk1/4 mature mRNAs by promoting splicing of the intron-retaining RNAs4.
1) Muraki et al. (2004), Manipulation of alternative splicing by a newly developed inhibitor of Clks; J. Biol. Chem., 279 24246
2) Foucourt et al. (2014), Design and synthesis of thiazolo[5,4-f]quinazolines as DYRK1A inhibitors, part II; Molecules, 19 15411
3) Nishida et al. (2011), Chemical treatment enhances skipping of a mutated exon in the dystrophin gene; Nat. Commun., 2 308
4) Ninomiya et al. (2011), Stress-responsive maturation of Clk1/4 pre-mRNAs promotes phosphorylation of SR splicing factor; J. Cell Biol., 195 27