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

Mardilovich, Katerina; Baugh, Mark; Crighton, Diane; Kowalczyk, Dominika; Gabrielsen, Mads; Munro, June; Croft, Daniel R.; Lourenço, Filipe C.; James, Daniel; Kalna, Gabriella; McGarry, Lynn; Rath, Oliver; Shanks, Emma; Garnett, Mathew J.; McDermott, Ultan; Brookfield, Joanna; Charles, Mark; Hammonds, Tim; Olson, Michael F.

doi:10.18632/oncotarget.6288

Cited by 39 publications

(45 citation statements)

References 41 publications

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“…These observations taken together are consistent with a collaborative role for actin filaments with microtubules in G 2 -M progression. This idea is further supported by the recent observation that anti-LIMK compounds synergize with vincristine in a model of neuroblastoma (31). Anti-LIMK compounds have been shown to increase the level of active cofilin, which in turn leads to an increase in cofilininduced severing of actin filaments (32).…”

Section: Discussionmentioning

confidence: 75%

Identification of Cancer-Targeted Tropomyosin Inhibitors and Their Synergy with Microtubule Drugs

Currier

Stehn

Swain

et al. 2017

Molecular Cancer Therapeutics

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Actin filaments, with their associated tropomyosin polymers, and microtubules are dynamic cytoskeletal systems regulating numerous cell functions. While antimicrotubule drugs are wellestablished, antiactin drugs have been more elusive. We previously targeted actin in cancer cells by inhibiting the function of a tropomyosin isoform enriched in cancer cells, Tpm3.1, using a first-in-class compound, TR100. Here, we screened over 200 other antitropomyosin analogues for anticancer and ontarget activity using a series of in vitro cell-based and biochemical assays. ATM-3507 was selected as the new lead based on its ability to disable Tpm3.1-containing filaments, its cytotoxicity potency, and more favorable drug-like characteristics. We tested ATM-3507 and TR100 alone and in combination with antimicrotubule agents against neuroblastoma models in vitro and in vivo. Both ATM-3507 and TR100 showed a high degree of synergy in vitro with vinca alkaloid and taxane antimicrotubule agents. In vivo, combination-treated animals bearing human neuroblastoma xenografts treated with antitropomyosin combined with vincristine showed minimal weight loss, a significant and profound regression of tumor growth and improved survival compared with control and either drug alone. Antitropomyosin combined with vincristine resulted in G 2 -M phase arrest, disruption of mitotic spindle formation, and cellular apoptosis. Our data suggest that small molecules targeting the actin cytoskeleton via tropomyosin sensitize cancer cells to antimicrotubule agents and are tolerated together in vivo. This combination warrants further study.

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Section: Discussionmentioning

confidence: 75%

Identification of Cancer-Targeted Tropomyosin Inhibitors and Their Synergy with Microtubule Drugs

Currier

Stehn

Swain

et al. 2017

Molecular Cancer Therapeutics

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“…Recently, it has been discovered that LIMK1 and LIMK2 modulate MT dynamics and, hence, mitosis . Mardilovich et al have made great strides in validating the importance of inhibiting LIMK and modulating MT structure. They demonstrated that two known LIMK inhibitors, CRT0105466 ( 67 ) and CRT0105950 ( 68 ), in combination with the MT‐destabilizing agent, vincristine, synergistically enhanced apoptosis in A549 cancer cells as compared with vincristine alone.…”

Section: Tubulin Kinase Dual Inhibition In Anticancer Treatmentmentioning

confidence: 99%

“…Lim kinases 1 and 2 (LIMK1 and LIMK2) have been well known to regulate cytoskeletal dynamics through modulating cofilin activity and, therefore, have an impact on cancer proliferation, survival, and metastasis. 172,173 LIMK activity has also been shown to contribute to the resistance of several chemotherapeutic agents as well as ionizing radiation. [174][175][176] Inhibition of LIMK has resulted in a reversal of drug resistance and enhancement of drug sensitivity.…”

Section: Lim Kinases 1 Andmentioning

confidence: 99%

“…The extensive research to identify LIMK inhibitors has led to a number of small molecules LIMK inhibitors with strong anticancer efficacy against diverse cancer cells, including breast, pancreatic, prostate, leukemia, and glioma among others. 172,[178][179][180][181][182] Recently, it has been discovered that LIMK1 and LIMK2 modulate MT dynamics and, hence, mitosis. 172 Mardilovich et al 172…”

Section: Lim Kinases 1 Andmentioning

confidence: 99%

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Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

Arnst

Banerjee

Chen

et al. 2019

Medicinal Research Reviews

122

107

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Microtubule (MT)‐targeting agents are highly successful drugs as chemotherapeutic agents, and this is attributed to their ability to target MT dynamics and interfere with critical cellular functions, including, mitosis, cell signaling, intracellular trafficking, and angiogenesis. Because MT dynamics vary in the different stages of the cell cycle, these drugs tend to be the most effective against mitotic cells. While this class of drug has proven to be effective against many cancer types, significant hurdles still exist and include overcoming aspects such as dose limited toxicities and the development of resistance. Newer generations of developed drugs attack these problems and alternative approaches such as the development of dual tubulin and kinase inhibitors are being investigated. This approach offers the potential to show increased efficacy and lower toxicities. This review covers different categories of MT‐targeting agents, recent advances in dual inhibitors, and current challenges for this drug target.

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“…An additional publication by Olson et al 18 will detail further biological data using compounds 22d and 3o (also known as CRT0105446 and CRT0105950 respectively) to investigate the effects of LIMK inhibition on microtubule organisation. The lead compounds are available externally for further profiling and investigation to determine their pharmacological applicability in conditions where LIMK plays a role.…”

Section: Figurementioning

confidence: 99%

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

Cited by 39 publications

References 41 publications

Identification of Cancer-Targeted Tropomyosin Inhibitors and Their Synergy with Microtubule Drugs

Identification of Cancer-Targeted Tropomyosin Inhibitors and Their Synergy with Microtubule Drugs

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

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

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