CCT241533 is an effective and selective ATP competitive inhibitor of CHK2 (Ki: 1.16 nM; IC50: 3 nM).

Chk1:245 nM, Chk2:3 nM, Chk2:1.16 nM (Ki)

CCT241533 inhibits CHK2 (IC50: 3 nM) and shows minimal cross-reactivity against a panel of kinases at 1 μM. X-ray crystallography confirms that CCT241533 binds to CHK2 in the ATP pocket. CCT241533 blocks CHK2 activity in human tumor cell lines in response to DNA damage. CCT241533 does not potentiate the cytotoxicity of a selection of genotoxic agents in several cell lines. However, CCT241533 significantly potentiates the cytotoxicity of two structurally distinct PARP inhibitors. Clear induction of the pS516 CHK2 signal is seen with a PARP inhibitor alone and this activation is abolished by CCT241533. In HT-29, HeLa, and MCF-7, the cytotoxicity of CCT241533 (GI50) is 1.7, 2.2, and 5.1 μM, respectively [1]. CCT241533 hydrochloride is a potent CHK2 inhibitor (IC50: 3 nM), with selectivity (63-fold) over CHK1(IC50: 190 nM) and low hERG inhibition (IC50: 22 μM) [2].