LIM kinase inhibitors disrupt mitotic microtubule organization and impair tumor cell proliferation.

Abstract

The actin and microtubule cytoskeletons are critically important for cancer cell proliferation, and drugs that target microtubules are widely-used cancer therapies. However, their utility is compromised by toxicities due to dose and exposure. To overcome these issues, we characterized how inhibition of the actin and microtubule cytoskeleton regulatory LIM kinases could be used in drug combinations to increase efficacy. A previously-described LIMK inhibitor (LIMKi) induced dose-dependent microtubule alterations that resulted in significant mitotic defects, and increased the cytotoxic potency of microtubule polymerization inhibitors. By combining LIMKi with 366 compounds from the GSK Published Kinase Inhibitor Set, effective combinations were identified with kinase inhibitors including EGFR, p38 and Raf. These findings encouraged a drug discovery effort that led to development of CRT0105446 and CRT0105950, which potently block LIMK1 and LIMK2 activity in vitro, and inhibit cofilin phosphorylation and increase αTubulin acetylation in cells. CRT0105446 and CRT0105950 were screened against 656 cancer cell lines, and rhabdomyosarcoma, neuroblastoma and kidney cancer cells were identified as significantly sensitive to both LIMK inhibitors. These large-scale screens have identified effective LIMK inhibitor drug combinations and sensitive cancer types. In addition, the LIMK inhibitory compounds CRT0105446 and CRT0105950 will enable further development of LIMK-targeted cancer therapy.

• Authors: Katerina Mardilovich, Mark Baugh, Diane Crighton, Dominika Kowalczyk, Mads Gabrielsen, June Munro, Daniel R Croft, Filipe Lourenco, Daniel James, Gabriella Kalna, Lynn McGarry, Oliver Rath, Emma Shanks, Mathew J Garnett, Ultan McDermott, Joanna Brookfield, Mark Charles, Tim Hammonds, Michael F Olson
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 36 Pg. 38469-86 (Nov 17 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26540348 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lim Kinases

Topics

• Breast Neoplasms (drug therapy, enzymology, pathology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, enzymology, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• Humans
• Lim Kinases (antagonists & inhibitors)
• Lung Neoplasms (drug therapy, enzymology, pathology)
• MCF-7 Cells
• Microtubules (metabolism)
• Mitosis (drug effects, physiology)
• Neoplasms (drug therapy, enzymology, pathology)
• Neuroblastoma (drug therapy, enzymology, pathology)