A novel orally active small molecule potently induces G(1) arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6

Cornell University, Итак, New York, United States
Cancer Research (Impact Factor: 9.28). 09/2006; 66(15):7661-7. DOI: 10.1158/0008-5472.CAN-06-1098
Source: PubMed

ABSTRACT Cell cycle deregulation is central to the initiation and fatality of multiple myeloma, the second most common hematopoietic cancer, although impaired apoptosis plays a critical role in the accumulation of myeloma cells in the bone marrow. The mechanism for intermittent, unrestrained proliferation of myeloma cells is unknown, but mutually exclusive activation of cyclin-dependent kinase 4 (Cdk4)-cyclin D1 or Cdk6-cyclin D2 precedes proliferation of bone marrow myeloma cells in vivo. Here, we show that by specific inhibition of Cdk4/6, the orally active small-molecule PD 0332991 potently induces G(1) arrest in primary bone marrow myeloma cells ex vivo and prevents tumor growth in disseminated human myeloma xenografts. PD 0332991 inhibits Cdk4/6 proportional to the cycling status of the cells independent of cellular transformation and acts in concert with the physiologic Cdk4/6 inhibitor p18(INK4c). Inhibition of Cdk4/6 by PD 0332991 is not accompanied by induction of apoptosis. However, when used in combination with a second agent, such as dexamethasone, PD 0332991 markedly enhances the killing of myeloma cells by dexamethasone. PD 0332991, therefore, represents the first promising and specific inhibitor for therapeutic targeting of Cdk4/6 in multiple myeloma and possibly other B-cell cancers.

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Available from: Scott Ely, Jan 08, 2015
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    • "Gene expression studies have shown that the overexpression of CCND3 and CCND1 results in a clustering of downstream gene expression suggesting that activation of these two genes results in the deregulation of common downstream transcriptional events [27]. Due to the seeming importance of cyclin D gene deregulation in myeloma, cyclin D inhibitors with a variety of specificities have shown promise targeting myeloma in vitro [40] [41], with many of these inhibitors now entering early human trials. Unlike í µí±¡(4; 14), the overall prognostic impact of these two translocations is neutral [42], although í µí±¡(11; 14) patients do show considerable heterogeneity and in some instances the translocation may manifest with an aggressive phenotype such as PCL. "
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    Advances in Hematology 04/2014; 2014:864058. DOI:10.1155/2014/864058
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    • "In recent years, a large number of selective Cdk4 inhibitors have been described in medicinal chemistry literature [14] [15] [16]. In this regard, VanderWel et al. [17] [18] identified various pyrido-[2,3-d]pyrimidin-7-ones derivatives as selective inhibitors of the Cdk4-cyclin D complex (IC 50 2– 32 nM). "
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