Chemically Diverse Group I p21-Activated Kinase (PAK) Inhibitors Impart Acute Cardiovascular Toxicity with a Narrow Therapeutic Window

p21-activated kinase 1 (PAK1) has
an important role in transducing
signals in several oncogenic pathways. The concept of inhibiting this
kinase has garnered significant interest over the past decade, particularly
for targeting cancers associated with PAK1 amplification. Animal studies
with the selective group I PAK (pan-PAK1, 2, 3) inhibitor G-5555 from
the pyrido­[2,3-d]­pyrimidin-7-one class uncovered
acute toxicity with a narrow therapeutic window. To attempt mitigating
the toxicity, we introduced significant structural changes, culminating
in the discovery of the potent pyridone side chain analogue G-9791.
Mouse tolerability studies with this compound, other members of this
series, and compounds from two structurally distinct classes revealed
persistent toxicity and a correlation of minimum toxic concentrations
and PAK1/2 mediated cellular potencies. Broad screening of selected
PAK inhibitors revealed PAK1, 2, and 3 as the only overlapping targets.
Our data suggest acute cardiovascular toxicity resulting from the
inhibition of PAK2, which may be enhanced by PAK1 inhibition, and
cautions against continued pursuit of pan-group I PAK inhibitors in
drug discovery.