Comparative Analysis of Small-Molecule LIMK1/2 Inhibitors: Chemical Synthesis, Biochemistry, and Cellular Activity

LIM
domain kinases 1 and 2 (LIMK1 and LIMK2) regulate actin dynamics
and subsequently key cellular functions such as proliferation and
migration. LIMK1 and LIMK2 phosphorylate and inactivate cofilin leading
to increased actin polymerization. As a result, LIMK inhibitors are
emerging as a promising treatment strategy for certain cancers and
neurological disorders. High-quality chemical probes are required
if the role of these kinases in health and disease is to be understood.
To that end, we report the results of a comparative assessment of
17 reported LIMK1/2 inhibitors in a variety of in vitro enzymatic and cellular assays. Our evaluation has identified three
compounds (TH-257, LIJTF500025, and LIMKi3) as potent and selective
inhibitors suitable for use as in vitro and in vivo pharmacological tools for the study of LIMK function
in cell biology.