title: 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.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK.
authors.forename: Katerina
authors.initials: K
authors.lastname: Mardilovich
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Baugh
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK.
authors.forename: Diane
authors.initials: D
authors.lastname: Crighton
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK.
authors.forename: Dominika
authors.initials: D
authors.lastname: Kowalczyk
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK.
authors.forename: Mads
authors.initials: M
authors.lastname: Gabrielsen
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK.
authors.forename: June
authors.initials: J
authors.lastname: Munro
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Croft
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK.
authors.forename: Filipe
authors.initials: F
authors.lastname: Lourenco
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: James
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Kalna
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK.
authors.forename: Lynn
authors.initials: L
authors.lastname: McGarry
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK.
authors.forename: Oliver
authors.initials: O
authors.lastname: Rath
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Shanks
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Mathew J
authors.initials: MJ
authors.lastname: Garnett
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Ultan
authors.initials: U
authors.lastname: McDermott
authors.affiliation: Cancer Research Technology Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Brookfield
authors.affiliation: Cancer Research Technology Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Charles
authors.affiliation: Cancer Research Technology Discovery Laboratories, London Bioscience Innovation Centre, London, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Hammonds
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Olson
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D054461:Lim Kinases / Q000037:antagonists & inhibitors*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D061986:MCF-7 Cells; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects* / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D009447:Neuroblastoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology
chemical_list: D054461:Lim Kinases
keywords: LIMK; cytoskeleton; inhibitor; kinase; microtubule