AI Article Synopsis
- Researchers optimized a series of compounds to identify a potent and selective oral CHK1 inhibitor for preclinical development, showing effectiveness as both a chemotherapy enhancer and a standalone treatment.
- The optimization process involved evaluating the compounds' cellular mechanisms to ensure selectivity, leading to the discovery of a highly selective ATP competitive inhibitor.
- It was determined that changes in lipophilicity and basicity influenced both CHK1 potency and potential side effects on the hERG ion channel, resulting in a compound with favorable pharmacokinetic properties and low expected doses for human use.
Article Abstract
Multiparameter optimization of a series of 5-((4-aminopyridin-2-yl)amino)pyrazine-2-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy as a potentiator of deoxyribonucleic acid (DNA) damaging chemotherapy and as a single agent. Cellular mechanism of action assays were used to give an integrated assessment of compound selectivity during optimization resulting in a highly CHK1 selective adenosine triphosphate (ATP) competitive inhibitor. A single substituent vector directed away from the CHK1 kinase active site was unexpectedly found to drive the selective cellular efficacy of the compounds. Both CHK1 potency and off-target human ether-a-go-go-related gene (hERG) ion channel inhibition were dependent on lipophilicity and basicity in this series. Optimization of CHK1 cellular potency and in vivo pharmacokinetic-pharmacodynamic (PK-PD) properties gave a compound with low predicted doses and exposures in humans which mitigated the residual weak in vitro hERG inhibition.
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| http://dx.doi.org/10.1021/acs.jmedchem.5b01938 | DOI Listing |
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