title: Novel LIMK2 Inhibitor Blocks Panc-1 Tumor Growth in a mouse xenograft model.
abstract: 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.
authors.affiliation: Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Roni
authors.initials: R
authors.lastname: Rak
authors.affiliation: Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Roni
authors.initials: R
authors.lastname: Haklai
authors.affiliation: Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Galit
authors.initials: G
authors.lastname: Elad-Tzfadia
authors.affiliation: The Blavatnik School of Computer Science, Raymond and Beverly Sackler Faculty of Exact Sciences.
authors.forename: Haim J
authors.initials: HJ
authors.lastname: Wolfson
authors.affiliation: School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences.
authors.forename: Shmuel
authors.initials: S
authors.lastname: Carmeli
authors.affiliation: Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Yoel
authors.initials: Y
authors.lastname: Kloog
keywords: LIMK; Rho; T56-LIMKi; cofilin; pancreatic cancer