Damnacanthal, an effective inhibitor of LIM-kinase, inhibits cell migration and invasion

Ohashi, Kazumasa; Sampei, Kaori; Nakagawa, Mami; Uchiumi, Naoto; Amanuma, Tatsuya; Aiba, Setsuya; Oikawa, Masato; Mizuno, Kensaku

doi:10.1091/mbc.e13-09-0540

Cited by 37 publications

(31 citation statements)

References 55 publications

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“…Damnacanthal suppressed LIMK1-induced cofilin phosphorylation, and inhibited migration and invasion MDA-MB-231 cell line. Topical application of damnacanthal also suppressed hapten-induced migration of epidermal Langerhans cells in mouse ears (65). These inhibitors provide useful tools for investigating the cellular and physiological functions of LIMKs and have a great potential for the development of agents against LIMK-related diseases.…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: Targeting the Kinase Effectors of RHO-Family GTPases

Prudnikova

Rawat

Chernoff

2015

Clinical Cancer Research

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RHO GTPases, members of the RAS superfamily of small GTPases, are adhesion and growth-factor activated molecular switches that play important roles in tumor development and progression. When activated, RHO-family GTPases such as RAC1, CDC42, and RHOA, transmit signals by recruiting a variety of effector proteins, including the protein kinases PAK, ACK, MLK, MRCK, and ROCK. Genetically-induced loss of RHO function impedes transformation by a number of oncogenic stimuli, leading to an interest in developing small molecule inhibitors that either target RHO GTPases directly, or that target their downstream protein kinase effectors. Although inhibitors of RHO GTPases and their downstream signaling kinases have not yet been widely adopted for clinical use, their potential value as cancer therapeutics continues to facilitate pharmaceutical research and development and is a promising therapeutic strategy.

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Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: Targeting the Kinase Effectors of RHO-Family GTPases

Prudnikova

Rawat

Chernoff

2015

Clinical Cancer Research

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“…In addition, LIMK1 has been described to present a tyrosine kinase activity [6, 7]. Thus, instead of being strictly serine/threonine kinases, LIMKs appear to have dual-specificity serine/threonine and tyrosine activities.…”

Section: Introductionmentioning

confidence: 99%

LIM kinases: cofilin and beyond

et al. 2017

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LIM kinases are common downstream effectors of several signalization pathways and function as a signaling node that controls cytoskeleton dynamics through the phosphorylation of the cofilin family proteins. These last 10 years, several reports indicate that the functions of LIM kinases are more extended than initially described and, specifically, that LIM kinases also control microtubule dynamics, independently of their regulation of actin microfilament. In this review we analyze the data supporting these conclusions and the possible mechanisms that could be involved in the control of microtubules by LIM kinases. The demonstration that LIM kinases also control microtubule dynamics has pointed to new therapeutic opportunities. Consistently, several new LIM kinase inhibitors have been recently developed. We provide a comprehensive comparison of these inhibitors, of their chemical structure, their specificity, their cellular effects as well as their effects in animal models of various diseases including cancer.

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“…8–12 Accumulated evidences suggest that Limk activity is associated with a variety of diseases including Williams Syndrome, 13 Alzheimer Disease (AD), 14, 15 psoriatic epidermal lesions, 16 primary pulmonary hypertension (PPH), 17, 18 intracranial aneurysms (IA), 19 ocular hypertension/glaucoma, 20 HIV and other viral infections, 21–24 and cancers and cancer cell migration/invasion. 25–31 …”

Section: Introductionmentioning

confidence: 99%

“…38, 39 Recently, a Japanese group also reported a Limk inhibitor (Damnacanthal or Dam, natural product based) from HTS campaigns, and this compound (Dam) has a Limk1 inhibition IC 50 of ~ 800 nM. 31 Lexicon pharmaceuticals revealed a class of Limk inhibitors based on a piperidine urea or guanidine scaffold for the treatment of ocular hypertension and associated glaucoma. 20 More recently, the same group of Lexicon scientists reported a novel class of Type-III binding Limk2 inhibitors that are based on a sulfonamide scaffold.…”

Section: Introductionmentioning

confidence: 99%

Bis-aryl Urea Derivatives as Potent and Selective LIM Kinase (Limk) Inhibitors

Yin

Zheng²,

Eid³

et al. 2015

J. Med. Chem.

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The discovery/optimization of bis-aryl ureas as Limk inhibitors to obtain high potency and selectivity, and appropriate pharmacokinetic properties through systematic SAR studies is reported. Docking studies supported the observed SAR. Optimized Limk inhibitors had high biochemical potency (IC50 < 25 nM), excellent selectivity against ROCK and JNK kinases (> 400-fold), potent inhibition of cofilin phosphorylation in A7r5,PC-3, and CEM-SS T cells (IC50 < 1 μM), and good in vitro and in vivo pharmacokinetic properties. In the profiling against a panel of 61 kinases, compound 18b at 1 μM inhibited only Limk1 and STK16 with ≥ 80% inhibition. Compounds 18b and 18f were highly efficient in inhibiting cell-invasion/migration in PC-3 cells. In addition, compound 18w was demonstrated to be effective on reducing intraocular pressure (IOP) on rat eyes. Taken together, these data demonstrated that we had developed a novel class of bis-aryl urea derived potent and selective Limk inhibitors.

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Damnacanthal, an effective inhibitor of LIM-kinase, inhibits cell migration and invasion

Cited by 37 publications

References 55 publications

Molecular Pathways: Targeting the Kinase Effectors of RHO-Family GTPases

Molecular Pathways: Targeting the Kinase Effectors of RHO-Family GTPases

LIM kinases: cofilin and beyond

Bis-aryl Urea Derivatives as Potent and Selective LIM Kinase (Limk) Inhibitors

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