LIM kinases (LIMKs) are important cell cytoskeleton regulators that play a prominent role in
cancer manifestation and neuronal diseases. The LIMK family consists of two homologues, LIMK1 and LIMK2, which differ from one another in expression profile, intercellular localization, and function. The main substrate of LIMK is
cofilin, a member of the
actin-depolymerizing factor (ADF)
protein family. When phosphorylated by LIMK,
cofilin is inactive. LIMKs play a contributory role in several
neurodevelopmental disorders and in
cancer growth and
metastasis. We recently reported the development and validation of a novel LIMK inhibitor, referred to here as
T56-LIMKi, using a combination of computational methods and classical biochemistry techniques. Here we report that
T56-LIMKi inhibits LIMK2 with high specificity, and shows little or no cross-reactivity with LIMK1. We found that
T56-LIMKi decreases phosphorylated
cofilin (p-
cofilin) levels and thus inhibits growth of several cancerous cell lines, including those of
pancreatic cancer,
glioma and
schwannoma. Because the most promising in-vitro effect of
T56-LIMKi was observed in the
pancreatic cancer cell line Panc-1, we tested the inhibitor on a nude mouse Panc-1 xenograft model.
T56-LIMKi reduced
tumor size and p-
cofilin levels in the Panc-1
tumors, leading us to propose
T56-LIMKi as a candidate
drug for
cancer therapy.