Design, synthesis and biological activity of new CDK4-specific inhibitors, based on fascaplysin

Aubry, Carine; Wilson, A. James; Jenkins, Paul R.; Mahale, Sachin; Chaudhuri, Bhabatosh; Maréchal, Jean‐Didier; Sutcliffe, Michael J.

doi:10.1039/b518019h

Cited by 41 publications

(31 citation statements)

References 24 publications

(21 reference statements)

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“…Before experimentally determined CDK4 structures became available, CDK4 homology models based on experimentally determined structures of CDK 2 and/or CDK6 were commonly used for computational studies such as ligand docking e.g. [34], [75]–[77] and molecular dynamics simulations [78]–[80]. Most small molecule CDK4 inhibitors are competitive inhibitors for ATP [81] and target the active form of CDK4.…”

Section: Resultsmentioning

confidence: 99%

FASCAPLYSIN as a Specific Inhibitor for CDK4: Insights from Molecular Modelling

2012

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Cyclin-dependent kinases (CDKs) play a key role in the cell cycle and are important anti-cancer drug targets. The natural product fascaplysin inhibits CDK4 with surprising selectivity (IC50 = 0.4 µM) compared to the close homolog CDK2 (IC50 = 500 µM). Free energy calculations of the positively charged fascaplysin and an uncharged iso-electronic derivative in the CDK2 and CDK4 inhibitor complexes indicate that the positive charge of fascaplysin is crucial for selectivity. This finding will guide further improvements in the design of fascaplysin-based selective inhibitors for CDK4.

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Section: Resultsmentioning

confidence: 99%

FASCAPLYSIN as a Specific Inhibitor for CDK4: Insights from Molecular Modelling

2012

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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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“…6566 N -methyltryptamine 25 was then formylated, giving compound 26 , and subsequently subjected to Danishefsky's nucleophilic tert -prenylation reaction to yield the reverse prenylated indole 27 . 67 This indole derivative was then selectively brominated with N -bromosuccinimide (NBS) in the presence of acid to afford the natural product flustrabromine 28 .…”

Section: Modulation Of Indole Controlled Phenotypes By Synthetic Indomentioning

confidence: 99%

Controlling bacterial behavior with indole-containing natural products and derivatives

2014

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Indole has recently been implicated as an important small molecule signal utilized by many bacteria to coordinate various forms of behavior. Indole plays a role in numerous bacterial processes, including: biofilm formation and maintenance, virulence factor production, antibiotic resistance and persister cell formation. Intercepting indole-signaling pathways with appropriately designed small molecules provides a n opportunity to control unwanted bacterial behaviors, and is an attractive anti-virulence therapeutic strategy. In this review, we give an overview of the process controlled by indole signaling, and summarize current efforts to design indole-containing small molecules to intercept these pathways, and detail the synthetic efforts towards accessing indole derived bioactive small molecules.

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Design, synthesis and biological activity of new CDK4-specific inhibitors, based on fascaplysin

Cited by 41 publications

References 24 publications

FASCAPLYSIN as a Specific Inhibitor for CDK4: Insights from Molecular Modelling

FASCAPLYSIN as a Specific Inhibitor for CDK4: Insights from Molecular Modelling

Targeting Cellular Proapoptotic Agents from Marine Sources

Controlling bacterial behavior with indole-containing natural products and derivatives

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