CCT241533

CCT241533 is a potent (biochemical IC50 3 nM) and selective (63-fold vs CHK1, >90% inhibition of 3 out of 85 kinases tested at 1 uM) inhibitor of CHK2. Mechanistic inhibition of CHK2 in cancer cells (HT29) has been demonstrated at concentrations from 1 uM (J Med Chem 2011, 54(2), 580-590) and further cell activity is described (Cancer Res 2011, 71(2), 463-472) at similar concentrations.

This probe has a very good selectivity profile; activity was found for only four kinases (PHK, GCK, MLKI, and MARK3) out of a panel of 85. The X-ray structure shows CCT241533 bound to CHK2 in the kinase domain region at a resolution of 2.3 Angstrom. Selectivity of CCT241533 for CHK2 over CHK1 is 80-fold. Pairing with PARP inhibitors enhances cellular toxicity. No PK data are available; solubility has been indicated in DMSO only. This probe is commercially available up to 100 mg of material, and scaled-up synthesis is possible.

CCT241533 is a selective, ATP-competitive CHEK2 inhibitor with biochemical (3 nM) and cellular activity. The compound also inhibits CHEK1 in vitro at 190-245 nM and potentiated the anti-proliferative effect of a PARP inhibitor in p53-minus cancer cells. The compound blocks CHEK2 autophosphorylation in response to DNA damage from bleomycin, etoposide, ionizing radiation in p53-null HT29 and HeLa cells, but not in p53 wild-type A549 cells. CCT241533 did not potentiate the cytotoxicity of bleomycin, however. The compound also blocked CHEK2 activity in three human tumor cell lines HT29 (GI₅₀=1.7 uM), HeLa (GI₅₀=2.2 uM) and MCF7 (GI₅₀=5.1 uM) and protected mouse thymocytes from apoptosis by ionizing radiation.