Discovery of a Potent and Selective Inhibitor of Cyclin-Dependent Kinase 4/6

Toogood, Peter L.; Harvey, Patricia J.; Repine, Joseph T.; Sheehan, D.; Vanderwel, Scott N.; Zhou, Hairong; Keller, Paul R.; McNamara, Dennis J.; Sherry, Debra; Zhu, Tong; Brodfuehrer, Joanne; Choi, Chung Sik; Barvian, Mark R.; Fry, David W.

doi:10.1021/jm049354h

Cited by 449 publications

(391 citation statements)

References 60 publications

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“…Mechanistically, these drug candidates inhibit CDK4/6, halt Rb phosphorylation and arrest G1 cell cycle progression of cancer cells. 51,[90][91][92][93] PD0332991 has also demonstrated to cause almost identical senescence phenotypes as the endogenous CDK inhibitors p16 INK4a and p21 Cip1 do. 94 PD0332991 is a pyridopyrimidine derivative ( Table 2) developed by Pfizer with relative high level of selectivity toward CDK4 and CDK6.…”

Section: Structural Features and Regulationmentioning

confidence: 97%

Targeting CDK6 in cancer: State of the art and new insights

et al. 2015

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Cyclin-dependent kinase 6 (CDK6) plays a vital role in regulating the progression of the cell cycle. More recently, CDK6 has also been shown to have a transcriptional role in tumor angiogenesis. Up-regulated CDK6 activity is associated with the development of several types of cancers. While CDK6 is over-expressed in cancer cells, it has a low detectable level in non-cancerous cells and CDK6-null mice develop normally, suggesting a specific oncogenic role of CDK6, and that its inhibition may represent an ideal mechanism-based and low toxic therapeutic strategy in cancer treatment. Identification of selective small molecule inhibitors of CDK6 is thus needed for drug development. Herein, we review the latest understandings of the biological regulation and oncogenic roles of CDK6. The potential clinical relevance of CDK6 inhibition, the progress in the development of small-molecule CDK6 inhibitors and the rational design of potential selective CDK6 inhibitors are also discussed.

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Section: Structural Features and Regulationmentioning

confidence: 97%

Targeting CDK6 in cancer: State of the art and new insights

et al. 2015

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“…Although numerous small molecule inhibitors have been developed with a more pointed interest in targeting the CDK2 kinase, recent data suggest that the cyclin D1/ CDK4 kinase may represent a good therapeutic target. CDK4/CDK6-specific small molecule inhibitors have been developed and one such molecule, PD 0332991, exhibits an IC50 in the nanomolar range, with excellent target specificity (Fry et al, 2004;Toogood et al, 2005). In addition, the cytostatic property of PD 0332991 is restricted to tumor-derived cell lines, which retain wildtype Rb and depend upon the cyclin D1/CDK kinase for proliferation (Fry et al, 2004).…”

Section: Conclusion and Lingering Questionsmentioning

confidence: 99%

Cyclin D1: polymorphism, aberrant splicing and cancer risk

et al. 2006

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The cyclin D1 proto-oncogene exercises powerful control over the mechanisms that regulate the mitotic cell cycle, and excessive cyclin D1 expression and/or activity is common in human cancers. Although somatic mutations of the cyclin D1 locus are rarely observed, mounting evidence demonstrates that a specific polymorphism of cyclin D1 (G/A870) and a protein product of a potentially related alternate splicing event (cyclin D1b) may influence cancer risk and outcome. Herein, we review the epidemiological and functional literatures that link these alterations of cyclin D1 to human tumor development and progression.

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“…Recently, a highly specific CDK4/6 inhibitor, PD-0332991 (PD), has been developed, and represents a viable mechanism for inhibition of D-type cyclin-mediated mitogenic/oncogenic signaling and subsequent activation of an RB-mediated checkpoint response (Toogood et al, 2005). This agent shows well-tolerated cytostatic function and specificity through targeting oncogenic events that function through the cyclin D/CDK4/6 axis, which should be relatively inactive in non-cycling neighboring 'normal' tissue.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure

et al. 2010

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A hallmark of cancer is the deregulation of cell-cycle machinery, ultimately facilitating aberrant proliferation that fuels tumorigenesis and disease progression. Particularly, in breast cancers, cyclin D1 has a crucial role in the development of disease. Recently, a highly specific inhibitor of CDK4/6 activity (PD-0332991) has been developed that may have efficacy in the treatment of breast cancer. To interrogate the utility of PD-0332991 in treating breast cancers, therapeutic response was evaluated on a panel of breast cancer cell lines. These analyses showed that the chronic loss of Rb is specifically associated with evolution to a CDK4/6-independent state and, ultimately, resistance to PD-0332991. However, to interrogate the functional consequence of Rb directly, knockdown experiments were performed in models that represent immortalized mammary epithelia and multiple subtypes of breast cancer. These studies showed a highly specific role for Rb in mediating the response to CDK4/6 inhibition that was dependent on transcriptional repression manifest through E2F, and the ability to attenuate CDK2 activity. Acquired resistance to PD-03322991 was specifically associated with attenuation of CDK2 inhibitors, indicating that redundancy in CDK functions represents a determinant of therapeutic failure. Despite these caveats, in specific models, PD-0332991 was a particularly effective therapy, which induced Rb-dependent cytostasis. Combined, these findings indicate the critical importance of fully understanding cell-cycle regulatory pathways in directing the utilization of CDK inhibitors in the clinic.

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Discovery of a Potent and Selective Inhibitor of Cyclin-Dependent Kinase 4/6

Cited by 449 publications

References 60 publications

Targeting CDK6 in cancer: State of the art and new insights

Targeting CDK6 in cancer: State of the art and new insights

Cyclin D1: polymorphism, aberrant splicing and cancer risk

Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure

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