Potent Inhibition of Cdc2 Kinase Activity by the Flavonoid L86-8275

Losiewicz, Michael D.; Carlson, B. A.; Kaur, Gurmeet; Sausville, Edward A.; Worland, Peter J.

doi:10.1006/bbrc.1994.1742

Cited by 303 publications

(167 citation statements)

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“…Therefore, targeting cdk activity has become an attractive strategy in cancer therapy, as it could potentially create a rationally designed inhibitor of a specific process that leads a cell to malignant transformation. To date, several families of chemical inhibitors targeted against different cdk activities have been described (Losiewicz et al, 1994;Gray et al, 1998) and, for some of them, their anticancer therapeutic potential has been demonstrated in preclinical studies (Dai and Grant, 2004). Recent attention has been focused on biological molecules, rather than chemotherapeutic agents, that combine the effectiveness of arresting cellular growth through interaction with important cell cycle checkpoint regulators, and the low risk of unexpected adverse reactions, thus improving clinical safety and patient tolerability.…”

Section: Discussionmentioning

confidence: 99%

A small molecule based on the pRb2/p130 spacer domain leads to inhibition of cdk2 activity, cell cycle arrest and tumor growth reduction in vivo

et al. 2006

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One strategy in the development of anticancer therapeutics has been to arrest malignant proliferation through inhibition of the enzymatic activity of cyclin-dependent kinases (cdks), which are key regulatory molecules of the cell cycle. Over the past few years, numerous compounds with remarkable cdk inhibitory activity have been studied in cancer therapy, although it is very difficult to point out the best cdk to target. An excellent candidate appears to be cdk2, whose alteration is a pathogenic hallmark of tumorigenesis. The small molecule described in our study showed an inhibitory effect on the kinase activity of cdk2, a significant growth arrest observed in a colony formation assay and a reduction in the size of the tumor in nude mice, thus suggesting its potential role as a promising new type of mechanism-based antitumor drug, also for the treatment of hyperproliferative disorders.

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Section: Discussionmentioning

confidence: 99%

A small molecule based on the pRb2/p130 spacer domain leads to inhibition of cdk2 activity, cell cycle arrest and tumor growth reduction in vivo

et al. 2006

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“…1) (also L-868275, HMR-1275, Alvocidib or NSC-649890) is a broad-range CDK inhibitor. It inhibits CDK1, CDK2, CDK4 and CDK7 at IC 50 value range of 0.04-0.4 M (Losiewicz et al 1994;Carlson et al 1996). It was Wrst discovered as epidermal growth factor receptor (EGFR) inhibitor, which inhibits at IC 50 value of 21 M. Later, it was shown that Xavopiridol could inhibit the growth of breast and lung cancer cell lines (Kaur et al 1992) and prostate, head and neck cancer and leukemia xenografts (Drees et al 1997;Patel et al 1998;Arguello et al 1998).…”

Section: Broad-range Inhibitorsmentioning

confidence: 99%

The CDK inhibitors in cancer research and therapy

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Valius²

2011

J Cancer Res Clin Oncol

220

176

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Chemical compounds that interfere with an enzymatic function of kinases are useful for gaining insight into the complicated biochemical processes in mammalian cells. Cyclin-dependent kinases (CDK) play an essential role in the control of the cell cycle and/or proliferation. These kinases as well as their regulators are frequently deregulated in diVerent human tumors. Aberrations in CDK activity have also been observed in viral infections, Alzheimer's, Parkinson's diseases, ischemia and some proliferative disorders. This led to an intensive search for small-molecule CDK inhibitors not only for research purposes, but also for therapeutic applications. Here, we discuss seventeen CDK inhibitors and their use in cancer research or therapy. This review should help researchers to decide which inhibitor is best suited for the speciWc purpose of their research. For this purpose, the targets, commercial availability and IC 50 values are provided for each inhibitor. The review will also provide an overview of the clinical studies performed with some of these inhibitors.

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“…Initial studies with this flavonoid revealed clear evidence of G 1 /S or G 2 /M arrest, due to loss in cdk1 and cdk2 (Kaur et al, 1992;Worland et al, 1993;Losiewicz et al, 1994). Studies using purified cdks showed that the inhibition observed is reversible and competitively blocked by ATP, with a K i of 41 nm (Kaur Worland et al, 1993;Losiewicz et al, 1994;Carlson et al, 1996a, b).…”

Section: Flavopiridolmentioning

confidence: 99%