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CHK2 is a checkpoint kinase involved in the ATM-mediated response to double-strand DNA breaks. Inhibitors of CHK2 may increase the efficacy of genotoxic cancer therapies. CCT241533 has been identified and characterized as a novel CHK2 kinase inhibitor.

In vitro: CCT241533 inhibited CHK2 with an IC50 of 3 nmol/L and showed minimal cross-reactivity against a panel of kinases at 1 mmol/L. CCT241533 did not potentiate the cytotoxicity of a selection of genotoxic agents in several cell lines [1]. Moreover, as the most potent CHK2 inhibitor identified in the series, CCT241533 showed potent selectivity (63-fold) over CHK1 and low hERG inhibition [2].

In silico: X-ray crystallography confirmed that CCT241533 bound to CHK2 in the ATP pocket. Overall, the binding mode was found to be very highly conserved relative to previous compounds, with all of the key hydrogen bond interactions maintained. The potency gained with CCT241533 therefore appeared to be due to the presence of the two methoxy substituents occupying the solvent exposed region of the enzyme, and contributions from the isopropyl alcohol substituent [2].

Clinical trial: No clinical data are available currently

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