TG003 | Clk family kinase inhibitor

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 cells.¹ 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 gene.³ TG003 increases levels of Clk1/4 mature mRNAs by promoting splicing of the intron-retaining RNAs.⁴

References/Citations:

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