Inhibition of cancer cell growth by cyclin dependent kinase 4 inhibitors synthesized based on the structure of fascaplysin

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

doi:10.1016/j.bioorg.2006.06.004

Cited by 20 publications

(21 citation statements)

References 24 publications

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“…Flavopiridol is a pan‐CDK inhibitor preferentially targeting CDK2/cyclin E activity and has shown clinical activity in phase I and II trials. A long‐standing goal has been to obtain specific CDK4/6 inhibitors and that objective is being addressed by several small molecule and natural product inhibitors, for example, PD 0332991, fascaplysin and fascaplysin analogues [Toogood et al, 2005; Mahale et al, 2006; Lin et al, 2007].…”

Section: Cyclin D‐cdk4/6: An Oncogene and Pharmacological Targetmentioning

confidence: 99%

Cyclin degradation for cancer therapy and chemoprevention

Freemantle

Liu

Feng

et al. 2007

J of Cellular Biochemistry

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Cancer is characterized by uncontrolled cell division resulting from multiple mutagenic events. Cancer chemoprevention strategies aim to inhibit or reverse these events using natural or synthetic pharmacologic agents. Ideally, this restores normal growth control mechanisms. Diverse classes of compounds have been identified with chemopreventive activity. What unites many of them is an ability to inhibit the cell cycle by specifically modulating key components. This delays division long enough for cells to respond to mutagenic damage. In some cases, damage is repaired and in others cellular damage is sufficient to trigger apoptosis. It is now known that pathways responsible for targeting G1 cyclins for proteasomal degradation can be engaged pharmacologically. Emergence of induced cyclin degradation as a target for cancer therapy and chemoprevention in pre-clinical models is discussed in this article. Evidence for cyclin D1 as a molecular pharmacologic target and biological marker for clinical response is based on experience of proof of principle trials.

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Section: Cyclin D‐cdk4/6: An Oncogene and Pharmacological Targetmentioning

confidence: 99%

Cyclin degradation for cancer therapy and chemoprevention

Freemantle

Liu

Feng

et al. 2007

J of Cellular Biochemistry

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“…SU9516 and Fascaplysin are pan-CDK inhibitors with selectivity for CDK2 and CDK4 in vitro and in vivo [29], [30]. Because the effect on cJun phosphorylation was observed between 0 and 6 hours, we focused on CDK4 due to its relatively early activity in initiating cell proliferation, and tested the role of CDK4 in c-Jun phosphorylation using more direct approaches.…”

Section: Resultsmentioning

confidence: 99%

CDK-Mediated Regulation of Cell Functions via c-Jun Phosphorylation and AP-1 Activation

Bush

Bishop

2011

PLoS ONE

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Cyclin-dependent kinases (CDKs) and their targets have been primarily associated with regulation of cell-cycle progression. Here we identify c-Jun, a transcription factor involved in the regulation of a broad spectrum of cellular functions, as a newly recognized CDK substrate. Using immune cells from mouse and human, and several complementary in vitro and in vivo approaches including dominant negative protein expression, pharmacologic inhibitors, kinase assays and CDK4 deficient cells, we demonstrate the ability of CDK4 to phosphorylate c-Jun. Additionally, the activity of AP-1, a ubiquitous transcription factor containing phosphorylated c-Jun as a subunit, was inhibited by abrogating CDK4. Surprisingly, the regulation of c-Jun phosphorylation by CDK4 occurred in non-dividing cells, indicating that this pathway is utilized for cell functions that are independent of proliferation. Our studies identify a new substrate for CDK4 and suggest a mechanism by which CDKs can regulate multiple cellular activation functions, not all of which are directly associated with cell cycle progression. These findings point to additional roles of CDKs in cell signaling and reveal potential implications for therapeutic manipulations of this kinase pathway.

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“…Different strategies have been employed in the search for good inhibitors but almost none of them have been successful due to their unspecificity and the subsequent side effects (Fry et al 2004; McInnes 2008; Menu et al 2008). Thus, there is emerging interest in developing new strategies to search for selective inhibitors of CDK4 and CDK6 for cancer chemotherapy (Mahale et al 2006). To this end, in this study we used a new set of bioinformatic tools to design CDK4 and CDK6 inhibitors that mimic their natural inhibitor p16 INK4a .…”

Section: Discussionmentioning

confidence: 99%

Cyclin-dependent kinases 4 and 6 control tumor progression and direct glucose oxidation in the pentose cycle

et al. 2011

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Cyclin-dependent kinases CDK4 and CDK6 are essential for the control of the cell cycle through the G1 phase. Aberrant expression of CDK4 and CDK6 is a hallmark of cancer, which would suggest that CDK4 and CDK6 are attractive targets for cancer therapy. Herein, we report that calcein AM (the calcein acetoxymethyl-ester) is a potent specific inhibitor of CDK4 and CDK6 in HCT116 human colon adenocarcinoma cells, inhibiting retinoblastoma protein (pRb) phosphorylation and inducing cell cycle arrest in the G1 phase. The metabolic effects of calcein AM on HCT116 cells were also evaluated and the flux between the oxidative and non-oxidative branches of the pentose phosphate pathway was significantly altered. To elucidate whether these metabolic changes were due to the inhibition of CDK4 and CDK6, we also characterized the metabolic profile of a CDK4, CDK6 and CDK2 triple knockout of mouse embryonic fibroblasts. The results show that the metabolic profile associated with the depletion of CDK4, CDK6 and CDK2 coincides with the metabolic changes induced by calcein AM on HCT116 cells, thus confirming that the inhibition of CDK4 and CDK6 disrupts the balance between the oxidative and non-oxidative branches of the pentose phosphate pathway. Taken together, these results indicate that low doses of calcein can halt cell division and kill tumor cells. Thus, selective inhibition of CDK4 and CDK6 may be of greater pharmacological interest, since inhibitors of these kinases affect both cell cycle progression and the robust metabolic profile of tumors.

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Inhibition of cancer cell growth by cyclin dependent kinase 4 inhibitors synthesized based on the structure of fascaplysin

Cited by 20 publications

References 24 publications

Cyclin degradation for cancer therapy and chemoprevention

Cyclin degradation for cancer therapy and chemoprevention

CDK-Mediated Regulation of Cell Functions via c-Jun Phosphorylation and AP-1 Activation

Cyclin-dependent kinases 4 and 6 control tumor progression and direct glucose oxidation in the pentose cycle

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