Abstract
1. We have previously described C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as cell permeable inhibitors of the KDM4 and KDM5 subfamilies of JmjC histone lysine demethylases.2. Although exemplar compound 1 exhibited moderate clearance in mouse liver microsomes, it was highly cleared in vivo due to metabolism by aldehyde oxidase (AO). Similar human and mouse AO-mediated metabolism was observed with the pyrido[3,4-d]pyrimidin-4(3H)-one scaffold and other C8-substituted derivatives.3. We identified the C2-position as the oxidation site by LC-MS and 1H-NMR and showed that C2-substituted derivatives are no longer AO substrates.4. In addition to the experimental data, these observations are supported by molecular modelling studies in the human AO protein crystal structure.
Highlights
Methylation and demethylation of lysine residues on the histone H3 tail constitute important epigenetic modifications that differentiate transcriptionally active and inactive chromatin (Kooistra & Helin, 2012; Shiau et al, 2013)
Pyrido[3,4-d]pyrimidin-4(3H)-one metabolism 773 which prompted us to investigate the pharmacokinetics of this compound in mice
The fact that compound 1 is a substrate of mouse aldehyde oxidase (AO) explains why mouse microsomal clearance failed to predict the in vivo clearance of this compound
Summary
Methylation and demethylation of lysine residues on the histone H3 tail constitute important epigenetic modifications that differentiate transcriptionally active and inactive chromatin (Kooistra & Helin, 2012; Shiau et al, 2013). These processes are highly deregulated in cancer offering opportunities for drug discovery and development (Helin & Dhanak, 2013; Hoffmann et al, 2012; Lohse et al, 2011). In addition to evaluating the potency of our inhibitors on various JmjC histone lysine demethylases, our assay cascade includes the assessment of their metabolic stability in liver microsomes. Once compound stability in mouse liver microsomes has been established, we evaluate the in vivo pharmacokinetics in mice following iv and po administration to select compounds suitable for further pharmacokinetic– pharmacodynamic testing
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