Engineering Selectivity for Reduced Toxicity of Bacterial Kinase Inhibitors Using Structure-Guided Medicinal Chemistry

摘要

Tuberculosis is a major global public health concern, and new drugs are needed to combat both the typical form and the increasingly common drug-resistant form of this disease. The essential tuberculosis kinase PknB is an attractive drug development target because of its central importance in several critical signaling cascades. A major hurdle in kinase inhibitor development is the reduction of toxicity due to nonspecific kinase activity in host cells. Here a novel class of PknB inhibitors was developed from hit aminopyrimidine 1 (GW779439X), which was originally designed for human CDK4 but failed to progress clinically because of high toxicity and low specificity. Replacing the pyrazolopyridazine headgroup of the original hit with substituted pyridine or phenyl headgroups resulted in a reduction of Cdk activity and a 3-fold improvement in specificity over the human kinome while maintaining PknB activity. This also resulted in improved microbiological activity and reduced toxicity in THP-1 cells and zebrafish.