CDK inhibitors in cancer therapy: what is next?

Malumbres, Marcos; Pevarello, Paolo; Barbacid, Mariano; Bischoff, James R.

doi:10.1016/j.tips.2007.10.012

Cited by 231 publications

(225 citation statements)

References 36 publications

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“…Accordingly, pursuits for the inhibitors, targeting the activity of CDK1, has been the intense area of research for last two decades. 19 CCNB1, the regulatory subunit of MPF, could specifically increases the activity of CDK1, further leading to a strong proliferation promotion in a variety of cancer cells. 10,20 Studies have also revealed that CCNB1 is highly expressed in various primary tumors, 5-9 including colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

Chk1-induced CCNB1 overexpression promotes cell proliferation and tumor growth in human colorectal cancer

Fang

Liang

et al. 2014

Cancer Biology & Therapy

139

115

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Section: Discussionmentioning

confidence: 99%

Chk1-induced CCNB1 overexpression promotes cell proliferation and tumor growth in human colorectal cancer

Fang

Liang

et al. 2014

Cancer Biology & Therapy

139

115

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“…2 Most human tumors display alterations in these regulators, and interphase Cdks were soon identified as possible anticancer targets. 2,3 However, the first generation of pan-Cdk inhibitors, such us flavopiridol and UCN-01, did not show clinical advantages due to its side effects. 4 The analysis of gene-targeted mouse models indicated that Cdk2, Cdk4 and Cdk6 are only essential for the proliferation of some specialized cells, suggesting that Cdk inhibitors are likely to produce certain toxicities by affecting specific cells.…”

Section: Cell Cycle Entrymentioning

confidence: 99%

“…4 The analysis of gene-targeted mouse models indicated that Cdk2, Cdk4 and Cdk6 are only essential for the proliferation of some specialized cells, suggesting that Cdk inhibitors are likely to produce certain toxicities by affecting specific cells. 3,[5][6][7] Nonetheless, Cdk4 inhibition may be effective to prevent Myc-induced skin tumors, 8 Rasinduced breast cancer 9 or K-Ras-induced non-small-cell lung carcinoma. 10 These results suggest that Cdk inhibition may be exploited in clinical settings taking into consideration the cellular context of the tumor and the pathogenic spectrum of their mutations.…”

Section: Cell Cycle Entrymentioning

confidence: 99%

“…1 Strong inhibition of Cdk1 is therefore likely to be toxic for normal cells, preventing useful therapeutic concentrations. 3 However, recent studies suggest the possible use of Cdk1 inhibitors in specific cellular settings. Cdk1 is implicated in DNA repair by homologous recombination, and it is essential for efficient formation of BRCA1 foci.…”

Section: Targeting Mitotic Entrymentioning

confidence: 99%

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Killing cells by targeting mitosis

2012

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Cell cycle deregulation is a common feature of human cancer. Tumor cells accumulate mutations that result in unscheduled proliferation, genomic instability and chromosomal instability. Several therapeutic strategies have been proposed for targeting the cell division cycle in cancer. Whereas inhibiting the initial phases of the cell cycle is likely to generate viable quiescent cells, targeting mitosis offers several possibilities for killing cancer cells. Microtubule poisons have proved efficacy in the clinic against a broad range of malignancies, and novel targeted strategies are now evaluating the inhibition of critical activities, such as cyclin-dependent kinase 1, Aurora or Polo kinases or spindle kinesins. Abrogation of the mitotic checkpoint or targeting the energetic or proteotoxic stress of aneuploid or chromosomally instable cells may also provide further benefits by inducing lethal levels of instability. Although cancer cells may display different responses to these treatments, recent data suggest that targeting mitotic exit by inhibiting the anaphase-promoting complex generates metaphase cells that invariably die in mitosis.As the efficacy of cell-cycle targeting approaches has been limited so far, further understanding of the molecular pathways modulating mitotic cell death will be required to move forward these new proposals to the clinic.

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“…Flavopiridol has shown clinical activity in chronic lymphocytic leukemia (26,27). SNS-032 is reported to be in phase I/II development in advanced breast cancer, melanoma, non-small cell lung cancer, and B-cell malignancies (28,29). Seliciclib is in phase II clinical studies in several indications (reviewed in ref.…”

Section: Introductionmentioning

confidence: 99%

Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines

Squires¹,

Feltell²,

Wallis³

et al. 2009

Molecular Cancer Therapeutics

155

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Cyclin-dependent kinases (CDK), and their regulatory cyclin partners, play a central role in eukaryotic cell growth, division, and death. This key role in cell cycle progression, as well as their deregulation in several human cancers, makes them attractive therapeutic targets in oncology. A series of CDK inhibitors was developed using Astex's fragment-based medicinal chemistry approach, linked to high-throughput X-ray crystallography. A compound from this series, designated AT7519, is currently in early-phase clinical development. We describe here the biological characterization of AT7519, a potent inhibitor of several CDK family members. AT7519 showed potent antiproliferative activity (40-940 nmol/L) in a panel of human tumor cell lines, and the mechanism of action was shown here to be consistent with the inhibition of CDK1 and CDK2 in solid tumor cell lines. AT7519 caused cell cycle arrest followed by apoptosis in human tumor cells and inhibited tumor growth in human tumor xenograft models. Tumor regression was observed following twice daily dosing of AT7519 in the HCT116 and HT29 colon cancer xenograft models. We show that these biological effects are linked to inhibition of CDKs in vivo and that AT7519 induces tumor cell apoptosis in these xenograft models. AT7519 has an attractive biological profile for development as a clinical candidate, and the tolerability and efficacy in animal models compare favorably with other CDK inhibitors in clinical development. Studies described here formed the biological rationale for investigating the potential therapeutic benefit of AT7519 in cancer patients. [Mol Cancer Ther 2009;8(2):324 -32]

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CDK inhibitors in cancer therapy: what is next?

Cited by 231 publications

References 36 publications

Chk1-induced CCNB1 overexpression promotes cell proliferation and tumor growth in human colorectal cancer

Chk1-induced CCNB1 overexpression promotes cell proliferation and tumor growth in human colorectal cancer

Killing cells by targeting mitosis

Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines

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