Identification of a nonkinase target mediating cytotoxicity of novel kinase inhibitors

Ross‐Macdonald, Petra; Silva, Heshani de; Guo, Qi; Xiao, Hong; Hung, Chen-Yi; Penhallow, Becky; Markwalder, Jay A.; He, Li; Attar, Ricardo M.; Lin, Teng Nan; Seitz, Steven P.; Tilford, Charles; Wardwell-Swanson, Judith; Jackson, Donald

doi:10.1158/1535-7163.mct-08-0826

Cited by 115 publications

(136 citation statements)

References 35 publications

(43 reference statements)

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“…In another experiment, we tested whether (N-[5-[2,6-dichloro-phenyl]-5-difluoromethyl-2H-pyrazol-3-yl]thiazol-2-yl)-isobutyramide, a recently described LIMK inhibitor (33,34), also called LIMKi (Fig. 6A), was able to stabilize microtubules.…”

Section: Limk Inhibition Causes Microtubule Stabilizationmentioning

confidence: 99%

Pharmacological Inhibition of LIM Kinase Stabilizes Microtubules and Inhibits Neoplastic Growth

et al. 2012

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The emergence of tumor resistance to conventional microtubule-targeting drugs restricts their clinical use. Using a cell-based assay that recognizes microtubule polymerization status to screen for chemicals that interact with regulators of microtubule dynamics, we identified Pyr1, a cell permeable inhibitor of LIM kinase, which is the enzyme that phosphorylates and inactivates the actin-depolymerizing factor cofilin. Pyr1 reversibly stabilized microtubules, blocked actin microfilament dynamics, inhibited cell motility in vitro and showed anticancer properties in vivo, in the absence of major side effects. Pyr1 inhibition of LIM kinase caused a microtubulestabilizing effect, which was independent of any direct effects on the actin cytoskeleton. In addition, Pyr1 retained its activity in multidrug-resistant cancer cells that were resistant to conventional microtubuletargeting agents. Our findings suggest that LIM kinase functions as a signaling node that controls both actin and microtubule dynamics. LIM kinase may therefore represent a targetable enzyme for cancer treatment.

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Section: Limk Inhibition Causes Microtubule Stabilizationmentioning

confidence: 99%

Pharmacological Inhibition of LIM Kinase Stabilizes Microtubules and Inhibits Neoplastic Growth

et al. 2012

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“…Bristol Myers Squibb reported that substituted pyrazoles with an aryl di-ortho chloro group were potent LIMK inhibitors. 13 Similarly we found that pyridines substituted with aryl rings adjacent to the thiazole ring provided substantial improvements in potency as in 3a which had a LIMK1 potency of 15 nM. Even more importantly compound 3a was active in the p-cofilin cellular assay with an IC50=3 µM.…”

mentioning

confidence: 54%

Discovery, Development, and SAR of Aminothiazoles as LIMK Inhibitors with Cellular Anti-Invasive Properties

Charles¹,

Brookfield²,

Ekwuru³

et al. 2015

J. Med. Chem.

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ABSTRACT:As part of a program to develop a small molecule inhibitor of LIMK, a series of aminothiazole inhibitors were discovered by high throughput screening. Scaffold hopping and subsequent SAR directed development led to a series of low nanomolar inhibitors of LIMK1 and LIMK2 that also inhibited the direct biomarker p-cofilin in cells and inhibited the invasion of MDA MB-231-luc cells in a matrigel inverse invasion assay.Tumour cell invasion and metastasis are the primary causes of mortality in cancer patients. During progression of tumour cells to a metastatic phenotype, they undergo a series of changes that begin with loss of contact inhibition and increased motility, allowing them to migrate from the primary tumour site, invade distant organs and induce neovascularization resulting in metastasis. 1 Despite numerous developments, cancer cell invasion and metastasis is still a poorly studied process. Most strategies to treat cancer do not rely on inhibiting invasion and metastasis as the primary phenotype due to the requirement for lengthy and complicated clinical trials. However a detailed understanding of the drivers of cancer cell invasion and migration is essential to develop new treatments for cancer patients. The LIM kinases (LIMK1 and LIMK2; collectively LIMK) are TKL kinases that act downstream of Rho GTPases. LIM kinases phosphorylate and inactivate the filamentous-actin severing protein cofilin. Cycles of cofilin inactivation and activation enable dynamic actin rearrangements that are required for cell motility (Figure 1). Once phosphorylated at Ser3 by the LIM kinases cofilin can no longer bind to actin leading to the accumulation of actin polymers. LIM kinases are therefore centrally positioned regulators of actin cytoskeletal dynamics and also play important roles in microtubule organization. 2,3 LIMK1 has been reported to play a key regulatory role in tumour cell invasion and the level of LIMK1 is increased in invasive breast, 4 prostate, 5 and pancreatic 6 cancer cell lines in comparison with less invasive cells. Overexpression of LIMK1 in MCF-7 and in MDA MB-231 human breast cancer cell lines increased their motility, while inhibition of LIMK1 activity in MDA MB-231 cells by expression of a dominant negative LIMK1 resulted in decreased motility and formation of osteolytic bone lesions in an animal model of tumour invasion. 7 As such, the LIM kinases have been proposed to be attractive drug targets to block tumour cell invasion and metastasis. A number of groups have previously reported inhibitors of the LIM kinases 9-13 as treatments for cancer and for their ability to lower intraocular pressure for glaucoma. Herein we describe the discovery and development of a series of LIMK inhibitors that demonstrate inhibition of p-cofilin and inhibit invasion of cancer cells in a 3D inverse invasion assay. We used a commercially available kinase Glo ® kit measuring ATP depletion using full length LIMK and cofilin to screen 60,000 compounds. 14 From this we identified two lead series, a series of pyrimid...

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“…Given that LIMK inhibitors have now been developed by a number of drug discovery efforts (20)(21)(22)(23)(24), it should be possible for thorough pharmacological proof of concept experiments to be undertaken to test the hypothesis that LIM kinases are valid cancer targets. Although the use of LIMK inhibitors to block cancer cell invasiveness and metastasis was one initial potential application (12), several recent reports indicate that they may be useful for treating primary tumors (21,25).…”

Section: Future Directionsmentioning

confidence: 99%

Targeting MRCK and LIMK kinases for cancer therapy

Olson¹

2014

AACR Education book

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Identification of a nonkinase target mediating cytotoxicity of novel kinase inhibitors

Cited by 115 publications

References 35 publications

Pharmacological Inhibition of LIM Kinase Stabilizes Microtubules and Inhibits Neoplastic Growth

Pharmacological Inhibition of LIM Kinase Stabilizes Microtubules and Inhibits Neoplastic Growth

Discovery, Development, and SAR of Aminothiazoles as LIMK Inhibitors with Cellular Anti-Invasive Properties

Targeting MRCK and LIMK kinases for cancer therapy

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