New Fascaplysin‐Based CDK4‐Specific Inhibitors: Design, Synthesis and Biological Activity.

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

doi:10.1002/chin.200450196

Cited by 3 publications

(5 citation statements)

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“…This has inspired the synthesis of nonplanar fascaplysin analogs in an attempt to eliminate the DNA intercalating property, thereby reducing its toxicity to normal cells (26). Similarly, the planar borregomycin B appears to be a general cytotoxin, whereas borregomycin A, which is rendered nonplanar by BorX2-catalyzed indole rearrangement followed by BorX3-catalyzed oxidation, appears to show more specificity in both the cell-based cytotoxicity assay and the kinase activity assay.…”

Section: Resultsmentioning

confidence: 99%

Discovery of indolotryptoline antiproliferative agents by homology-guided metagenomic screening

Chang

Brady

2013

Proc. Natl. Acad. Sci. U.S.A.

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Natural product discovery by random screening of broth extracts derived from cultured bacteria often suffers from high rates of redundant isolation, making it ever more challenging to identify novel biologically interesting natural products. Here we show that homology-based screening of soil metagenomes can be used to specifically target the discovery of new members of traditionally rare, biomedically relevant natural product families. Phylogenetic analysis of oxy-tryptophan dimerization gene homologs found within a large soil DNA library enabled the identification and recovery of a unique tryptophan dimerization biosynthetic gene cluster, which we have termed the bor cluster. When heterologously expressed in Streptomyces albus, this cluster produced an indolotryptoline antiproliferative agent with CaMKIIδ kinase inhibitory activity (borregomycin A), along with several dihydroxyindolocarbazole anticancer/antibiotics (borregomycins B-D). Similar homology-based screening of large environmental DNA libraries is likely to permit the directed discovery of new members within other previously rare families of bioactive natural products.antitumor | uncultured microbes | bisindole alkaloid | indenotryptoline

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Section: Resultsmentioning

confidence: 99%

Discovery of indolotryptoline antiproliferative agents by homology-guided metagenomic screening

Chang

Brady

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Compound 5 , on reaction with 4-biphenyl carbonyl chloride ( 6 ), produced compound 1 . The detailed lead optimization and SAR have been described in previous publications. − Scheme shows the synthesis of compound 1 . It is worth noting that nonplanar analogues with opened C and D rings of fascaplysin ( 2 ) demonstrated a loss of DNA intercalation activity.…”

Section: Resultsmentioning

confidence: 99%

“…The in vitro kinase assays for testing against Cdk4–cyclin D1, Cdk2–cyclin A, Cdk2–cyclin E, Cdk1–cyclin B1, and Cdk9–cyclin T1 were performed in-house. The methodology and results have been reported previously. − The kinase profiling for 58 representative kinases was done commercially at Millipore Bioscience Division, UK.…”

Section: Methodsmentioning

confidence: 99%

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Biphenyl-4-carboxylic Acid [2-(1H-Indol-3-yl)-ethyl]-methylamide (CA224), a Nonplanar Analogue of Fascaplysin, Inhibits Cdk4 and Tubulin Polymerization: Evaluation of in Vitro and in Vivo Anticancer Activity

Mahale

Bharate²,

Manda³

et al. 2014

J. Med. Chem.

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Biphenyl-4-carboxylic acid-[2-(1H-indol-3-yl)-ethyl]-methylamide 1 (CA224) is a nonplanar analogue of fascaplysin (2) that specifically inhibits Cdk4-cyclin D1 in vitro. Compound 1 blocks the growth of cancer cells at G0/G1 phase of the cell cycle. It also blocks the cell cycle at G2/M phase, which is explained by the fact that it inhibits tubulin polymerization. Additionally, it acts as an enhancer of depolymerization for taxol-stabilized tubulin. Western blot analyses of p53-positive cancer cells treated with compound 1 indicated upregulation of p53, p21, and p27 proteins together with downregulation of cyclin B1 and Cdk1. Compound 1 selectively induces apoptosis of SV40 large T-antigen transformed cells and significantly reduces colony formation efficiency, in a dose-dependent manner, of lung cancer cells. It is efficacious at 1/10th of the MTD against human tumors derived from HCT-116 and NCI-H460 cells in SCID mouse models. The promising efficacy of compound 1 in human xenograft models as well as its excellent therapeutic window indicates its potential for clinical development.

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“…Importantly, we demonstrated that the use of a cdk4 specific drug, Fascaplysin, resulted in decreased BRCA1 phosphorylation in vivo. There has long been a search for cdk4 inhibitors and more potent derivatives of Fascaplysin are currently being developed (Aubry et al, 2004). In addition, cdk inhibitors have been potentially useful chemotherapeutic agents that have progressed into phase III clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Functional consequences of cyclin D1/BRCA1 interaction in breast cancer cells

et al. 2007

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The inheritance of one defective BRCA1 or BRCA2 allele predisposes an individual to developing breast and ovarian cancers. BRCA1 is a multifunctional tumor suppressor protein, which through interaction with a vast array of proteins has implications in processes such as cell cycle, transcription, DNA damage response and chromatin remodeling. Conversely, the oncogene, cyclin D1 is overexpressed in about 35% of all breast cancer cases. In this study, we provide detailed analyses on the phosphorylation state of BRCA1 by cyclin D1/cdk4 complexes. In particular, we have identified Ser 632 of BRCA1 as a cyclin D1/cdk4 phosphorylation site in vitro. Using chromatin immunoprecipitation assays, we observed that the inhibition of cyclin D1/cdk4 activity resulted in increased BRCA1 DNA binding at particular promoters in vivo. In addition, we identified multiple novel genes that are bound by BRCA1 in vivo. Collectively, these results indicate that cyclin D1/cdk4-mediated phosphorylation of BRCA1 inhibits the ability of BRCA1 to be recruited to particular promoters in vivo. Therefore, cyclin D1/Cdk4 phosphorylation of BRCA1 could provide a mechanism to interfere with the DNA-dependent activities of BRCA1.

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New Fascaplysin‐Based CDK4‐Specific Inhibitors: Design, Synthesis and Biological Activity.

Cited by 3 publications

References 1 publication

Discovery of indolotryptoline antiproliferative agents by homology-guided metagenomic screening

Discovery of indolotryptoline antiproliferative agents by homology-guided metagenomic screening

Biphenyl-4-carboxylic Acid [2-(1H-Indol-3-yl)-ethyl]-methylamide (CA224), a Nonplanar Analogue of Fascaplysin, Inhibits Cdk4 and Tubulin Polymerization: Evaluation of in Vitro and in Vivo Anticancer Activity

Functional consequences of cyclin D1/BRCA1 interaction in breast cancer cells

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