Small molecule modulators of cyclin-dependent kinases for cancer therapy

Senderowicz, Adrian M.

doi:10.1038/sj.onc.1204085

Cited by 111 publications

(81 citation statements)

References 62 publications

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“…Examples of this class include flavopiridol, roscovitine, aminothiazole, UCN-01 (7-hydroxystaurosporine), and alsterpaullone (See Figure 2). The second class are compounds that modulate cdk activity by targeting the regulatory upstream pathways that govern cdk activity: by altering the expression and synthesis of the cdk/cyclin subunits or the cdk inhibitory proteins; by modulating the phosphorylation of cdk's; by targeting cdk-activating (Senderowicz, 2000;Senderowicz, 2002a, b). Examples for this class of compounds include perifosine and UCN-01, among others.…”

Section: Manipulation Of Cdk Activity For Therapeutic Purposesmentioning

confidence: 99%

“…Small molecular endogenous cdk inhibitors (SCDKI) are compounds that directly target the catalytic cdk subunit. Most of these compounds modulate cdk activity by interacting specifically with the ATP-binding site of cdk's (De Azevedo et al, 1997;Meijer and Kim, 1997;Zaharevitz et al, 1999;Senderowicz, 2000;Senderowicz, 2002b). Examples of this class include flavopiridol, roscovitine, aminothiazole, UCN-01 (7-hydroxystaurosporine), and alsterpaullone (See Figure 2).…”

Section: Manipulation Of Cdk Activity For Therapeutic Purposesmentioning

confidence: 99%

“…These strategies are divided into direct effects on the catalytic cdk subunit or indirect modulation of regulatory pathways that govern cdk activity (Senderowicz, 2000;. Small molecular endogenous cdk inhibitors (SCDKI) are compounds that directly target the catalytic cdk subunit.…”

Section: Manipulation Of Cdk Activity For Therapeutic Purposesmentioning

confidence: 99%

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Small-molecule cyclin-dependent kinase modulators

2003

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Section: Manipulation Of Cdk Activity For Therapeutic Purposesmentioning

confidence: 99%

Section: Manipulation Of Cdk Activity For Therapeutic Purposesmentioning

confidence: 99%

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Small-molecule cyclin-dependent kinase modulators

2003

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“…[2][3][4] Other agents such as the cyclin-dependent kinase inhibitors, flavopiridol, 7-hydroxystaurosporine (UCN-01) and staurosporine are at different phases of clinical development. 5,6 Additional attractive targets for intracellular signaling inhibition are modulators of the PKC family of isoenzymes. Perihydroxylated perylene quinones constitute a unique class of photoactivated inhibitors of ser/thr kinases.…”

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confidence: 99%

Antimetastatic activity of the photodynamic agent hypericin in the dark

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Lavie²,

Mandel³

et al. 2004

Intl Journal of Cancer

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A unique property of the photodynamic signal transduction inhibitor hypericin (HY) is high functionality in the dark, which has been shown to result in portfolio of anticancer activities both in vitro and in vivo. Here we show that treatment with HY significantly reduces growth rate of metastases in 2 murine models: breast adenocarcinoma (DA3) and squamous cell carcinoma (SQ2 Cancer is currently viewed as a cell cycle disease. Strategies to treat malignancies are thus shifting from toxic chemotherapy to agents that switch-off positive cell replication transducers specifically or to activators of endogenous negative cell cycle regulators (p53, p21 waf1 , Kip and INK families of proteins). 1 The feasibility of the novel approach is exemplified by recent success in achieving clinical remissions by Imatinib Mesylate (Gleevec), a rationally designed catalytic domain inhibitor of Abl, c-Kit and PDGFR tyrosine kinases. [2][3][4] Other agents such as the cyclin-dependent kinase inhibitors, flavopiridol, 7-hydroxystaurosporine (UCN-01) and staurosporine are at different phases of clinical development. 5,6 Additional attractive targets for intracellular signaling inhibition are modulators of the PKC family of isoenzymes. Perihydroxylated perylene quinones constitute a unique class of photoactivated inhibitors of ser/thr kinases. In this group, hypericin (HY) has been reported to inhibit PKC, 7,8 Erk1/2 kinases and also epidermal growth factor receptor tyrosine kinase. 9 -11 Most of these signaltransduction inhibitory activities of hypericin have been attributed to the photodynamic properties of the compound that were achieved when HY was excited by light at wavelengths absorbed by the molecule. 11 However, recent observations suggest that HY, in addition to its light-dependent anticancer activities, 12 possesses potent anticancer activities and ability to inhibit different signal transduction pathways also in the absence of light activation (dark effects). [13][14][15] We recently demonstrated that the newly identified anti-cancer activities of HY in the dark differ from the well-characterized light-induced effects of the compound in kinetics, modes of tumor cell death and their underling mechanisms. 13 Cell death induction by HY with light occurs rapidly. Within hours after light irradiation, cells undergo apoptosis, or if the light dose is high, also necrosis. In the dark, on the other hand, tumor cell exposure to HY is required for at least 48 hr in order to inhibit cell proliferation. At higher HY concentrations (Ͼ 10 M), the compound killed the tumor cells in the dark via mitotic cell death. 16 Mitotic cell death is a process observed in cancer cells following treatment with different chemotherapeutic agents as well as radiotherapy. The phenomenon is characterized by cells accumulation at G 2 /M, uncoupling of apoptosis, increased cell volume and multinucleation leading to cell death. 17 Although the precise mechanisms leading to mitotic cell death are not fully understood, we have recently identified processes by wh...

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“…It is noteworthy that protein kinases, which belong to transferases, have successfully been targeted by drugs for several decades, and it is likely that this trend will continue in the future. Currently, dozens of inhibitors are undergoing clinical trials against protein kinases and several drugs have been launched commercially [44][45][46][47][48][49][50] , demonstrating that protein kinases are one of the most important groups of drug targets. Therefore, enzymes, especially protein kinases, should also be emphasized in the pipeline for target validation.…”

Section: Novel Drug Target Predictionmentioning

confidence: 99%

Multi-algorithm and multi-model based drug target prediction and web server

Liu

Huang

et al. 2014

Acta Pharmacol Sin

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Aim: To develop a reliable computational approach for predicting potential drug targets based merely on protein sequence. Methods: With drug target and non-target datasets prepared and 3 classification algorithms (Support Vector Machine, Neural Network and Decision Tree), a multi-algorithm and multi-model based strategy was employed for constructing models to predict potential drug targets. Results: Twenty one prediction models for each of the 3 algorithms were successfully developed. Our evaluation results showed that ~30% of human proteins were potential drug targets, and ~40% of putative targets for the drugs undergoing phase II clinical trials were probably non-targets. A public web server named D3TPredictor (http://www.d3pharma.com/d3tpredictor) was constructed to provide easy access. Conclusion: Reliable and robust drug target prediction based on protein sequences is achieved using the multi-algorithm and multimodel strategy.

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Small molecule modulators of cyclin-dependent kinases for cancer therapy

Cited by 111 publications

References 62 publications

Small-molecule cyclin-dependent kinase modulators

Small-molecule cyclin-dependent kinase modulators

Antimetastatic activity of the photodynamic agent hypericin in the dark

Multi-algorithm and multi-model based drug target prediction and web server

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