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

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.