Toxicological evaluation of an inhaled IKK2 inhibitor (AZD2230) for treatment of Chronic Obstructive Pulmonary Disease (COPD) showed mutagenic effects in mammalian (Mouse Lymphoma Assay - MLA) and bacterial (Ames) in vitro genotoxicity tests. The five strain Ames genotoxicity tests demonstrated that AZD2230 is positive only in one particular strain, TA1537, with and without S9. This strain is responsive to simple intercalators, which target a monotonous run of guanine residues in the hisC3076 allele. Indeed, AZD2230 fits the current portrayal of typical nonclassical DNA intercalators that have a nearly planar aromatic system with at least two aromatic rings plus a basic center. We describe lead re-optimization efforts to remove compound genotoxicity, while retaining a number of important compound properties, including the primary IKK2 potency, lipophilicity, PBMC cell potency, selectivity, lung retention, binding to the OCT-1 transporter and in vivo potency. Molecular modeling of DNA intercalation played the key role in these efforts. The DNA intercalation was studied by force-field calculations using the B-DNA icosamer duplex dG<sub>20</sub>/dC<sub>20</sub> model, high quality OPLS2.1 force field and the GB/SA implicit solvation model. Aromatic systems of mutagenic molecules fit to the intercalation site and cause minimal disturbances on the locations of the B-DNA phosphate groups. Extension of the longest dimension of compounds is an effective tool to prevent genotoxicity in the TA1537 assay. Optimized compounds retain the desired properties and are non-mutagenic in the TA1537 and MLA assays.

B-DNA structure-based removal of genotoxicity from a series of inhibitors of the IκB-kinase IKK2

249th National Meeting (2015)

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