Fascaplysin-inspired diindolyls as selective inhibitors of CDK4/cyclin D1

Aubry, Carine; Wilson, A. James; Emmerson, Daniel P. G.; Murphy, Emma J.; Chan, Yu Yam; Dickens, Michael P.; García, Marcos D.; Jenkins, Paul R.; Mahale, Sachin; Chaudhuri, Bhabatosh

doi:10.1016/j.bmc.2009.06.070

Cited by 42 publications

(28 citation statements)

References 35 publications

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“…1A) but only slightly decreased cell viability (less than 30% inhibition) (Fig. 1B): VEGFR2 inhibitor IV (CAS 216661-57-3), Syk inhibitor III (CAS 1485-00-3), DMBI (CAS 5812-07-7, a PDGFR inhibitor), and fascaplysin (CAS 114719-57-2, a selective Cdk4/cyclin D1 inhibitor) [15].…”

Section: Resultsmentioning

confidence: 98%

Cyclin-Dependent Kinase 4 Phosphorylates and Positively Regulates PAX3-FOXO1 in Human Alveolar Rhabdomyosarcoma Cells

Liu

Ong

et al. 2013

PLoS ONE

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Alveolar rhabdomyosarcoma (ARMS) is an aggressive childhood muscle sarcoma with a 5-year survival rate of less than 30%. More than 80% of ARMSs harbor a PAX3-FOXO1 fusion transcription factor. However, expression of PAX3-FOXO1 in muscle cells alone is not sufficient and requires the loss of function of Ink4a/ARF to promote malignant proliferation of muscle cells in vitro or initiate ARMS tumor formation in vivo. This prompted us to examine the signaling pathways required to activate the function of PAX3-FOXO1 and to explore the functional interaction between the Ink4a/ARF and PAX3-FOXO1 signaling pathways. Here we report that inhibition of cyclin-dependent kinase 4 (Cdk4) by fascaplysin (a small molecule selective inhibitor of Cdk4/cyclin D1 that we identified in a screen for compounds that inhibit PAX3-FOXO1) led to inhibition of the transcriptional activity of PAX3-FOXO1 in ARMS cell line Rh30. Consistent with this finding, activation of Cdk4 enhanced the activity of PAX3-FOXO1. In vitro kinase assays revealed that Cdk4 directly phosphorylated PAX3-FOXO1 at Ser430. Whereas fascaplysin did not affect the protein level of PAX3-FOXO1, it did increase the cytoplasmic level of PAX3-FOXO1 in a portion of cells. Our findings indicate that Cdk4 phosphorylates and positively regulates PAX3-FOXO1 and suggest that inhibition of Cdk4 activity should be explored as a promising avenue for developing therapy for ARMS.

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Section: Resultsmentioning

confidence: 98%

Cyclin-Dependent Kinase 4 Phosphorylates and Positively Regulates PAX3-FOXO1 in Human Alveolar Rhabdomyosarcoma Cells

Liu

Ong

et al. 2013

PLoS ONE

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“…The reactions for synthesis of 1-(1H-indol-3-yl)-2-(4-diarylmethylpiperazine-1-yl)ethane-1,2-dione derivatives (19-30) are summarised in Scheme 1. Compounds 4-6 were prepared from indole and oxalyl chloride in anhydrous ether at 0∼ 5 ∘ C under the protection of nitrogen [7]. Compounds 7-10 were obtained from diaryl ketones in the presence of sodium borohydride in methanol at reflux [8].…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Anticancer Activity of 1-(1H-Indol-3-yl)-2-(4-diarylmethylpiperazine-1-yl)ethane-1,2-dione Derivatives

Jiang

2016

Journal of Chemistry

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Several new 1-(4-diarylmethylpiperazine-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione derivatives were synthesized by acylation of 1-diarylmethylpiperazine with 2-(1H-indol-3-yl)-2-oxoacetyl chloride. Their structures were confirmed by1H NMR, IR, mass spectra, and elemental analysis. These compounds were further evaluated for their anticancer activity, and most of them were found to have moderate-to-potent antiproliferative activities against Hela, A-549, and ECA-109 cancer cell linesin vitro.

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“…Since decrease in the Cdk4 activity, fascaplysin has also been revealed to be capable of inhibiting angiogenesis [92]. Based on the structure of fascaplysin, many compounds have been developed and some of them are more specific for, or more potent in, inhibiting Cdk4 activity, thus having a better potential to be new chemotherapeutic agents [93][94][95].…”

Section: Compounds That Disturbs the Growth Receptor Signaling Pathwaymentioning

confidence: 99%

Targeting Cellular Proapoptotic Agents from Marine Sources

Liu

Lin

Zheng

2014

Handbook of Anticancer Drugs From Marine Origin

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Marine organisms are an important source for the discovery of anticancer agents. In recent years, an increasing number of lead compounds have been isolated and some of them possess potent apoptosis-inducing activities in cancer cells. Apoptosis is a form of programmed cell death and is a critical defense mechanism against the occurrence of cancer. There is a long list of pro-or anti-apoptotic molecules that can trigger apoptosis. Therefore, searching agents that target these proor anti-apoptotic molecules has become an important strategy for the anticancer agent developments. This review summarizes some of marine-derived agents with pro-apoptotic activities and discusses the existing challenges and our perspectives on the development of anticancer agents from marine source.

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Fascaplysin-inspired diindolyls as selective inhibitors of CDK4/cyclin D1

Cited by 42 publications

References 35 publications

Cyclin-Dependent Kinase 4 Phosphorylates and Positively Regulates PAX3-FOXO1 in Human Alveolar Rhabdomyosarcoma Cells

Cyclin-Dependent Kinase 4 Phosphorylates and Positively Regulates PAX3-FOXO1 in Human Alveolar Rhabdomyosarcoma Cells

Synthesis and Anticancer Activity of 1-(1H-Indol-3-yl)-2-(4-diarylmethylpiperazine-1-yl)ethane-1,2-dione Derivatives

Targeting Cellular Proapoptotic Agents from Marine Sources

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