Cyclin-Dependent Kinase 4/6 (Cdk4/6) Inhibitors: Perspectives in Cancer Therapy and Imaging

Graf, Franziska; Mosch, Birgit; Koehler, Lena; Bergmann, Ralf; Wuest, Frank; Pietzsch, Jens

doi:10.2174/138955710791384072

Cited by 30 publications

(18 citation statements)

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“…1,9,10 For example, CDK4/6 is hyperactivated in a number of human cancers as a result of overexpression of positive regulators such as cyclin D or deletion and/or epigenetic alterations of substrates such as RB. 1,9,10 In addition, mutations and chromosomal translocations in the CDK4 locus have also been described. One prominent example is the CDK4 R24C mutation that results in insensitivity of CDK4 to INK4 family inhibitors and was first described in patients with familial melanoma.…”

Section: Introductionmentioning

confidence: 99%

Discovery of 8-Cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a Potent Inhibitor of Cyclin-Dependent Kinase 4 (CDK4) and AMPK-Related Kinase 5 (ARK5)

et al. 2014

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The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological approaches for developing multi kinase inhibitors with low toxicity profiles. With this goal in mind, we analyzed more than 150 novel cyano pyridopyrimidine compounds and identified structure activity relationship trends that can be exploited in the design of potent kinase inhibitors. One compound, 8-Cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) was found to be the most active, inducing apoptosis of tumor cells at a concentration of approximately 30–100nM. In vitro kinase profiling revealed that 7x is a multi-kinase inhibitor with potent inhibitory activity against the CDK4/CYCLIN D1 and ARK5 kinases. Here, we report the synthesis, structure activity relationship, kinase inhibitory profile, in vitro cytotoxicity and in vivo tumor regression studies by this lead compound.

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Section: Introductionmentioning

confidence: 99%

Discovery of 8-Cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a Potent Inhibitor of Cyclin-Dependent Kinase 4 (CDK4) and AMPK-Related Kinase 5 (ARK5)

et al. 2014

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“…Moreover, activation of the cyclin-dependent kinase machinery is required for the activation of cell division and cell proliferation as well as normal meiotic progression during porcine oocyte maturation (Fujii et al 2011;Bertoli et al 2013). Therefore, abnormal activity and/or expression of Cdkn are determined as the most important players in the induction of improper cell proliferation and carcinogenesis (Graf et al 2010). However, it was also found that these proteins may play an important role during oocyte maturation, embryo development and foetal growth, where cell division regulation is crucial for normal growth (Gotoh et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Expression of cyclin-dependent kinase inhibitors (CDKN1, CDKN5) in developmentally competent and incompetent porcine oocytes

Piotrowska¹,

Kempisty²,

Bukowska³

et al. 2013

Vet. Med.

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Although several reports have been published regarding the cyclin-dependent kinases (Cdks) in developmentally competent mammalian oocytes, still little is known about their expression pattern in developmentally incompetent female gametes. Since Cdks are the main cell cycle division regulators, also described as "checkpoints" in the MI to MII transition, the aim of this study was to investigate the differential mRNA expression of genes encoding Cdkn1 and Cdkn5 in developmentally competent and incompetent porcine oocytes. Porcine cumulus-oocyte complexes (COCs) were collected from crossbred Landrace gilts after slaughter and partly subjected to brilliant cresyl blue (BCB) staining and in vitro maturation (IVM). Three groups of COCs were analysed: (i) oocytes soon after collection without BCB staining, (ii) oocytes which remained colourless after staining (BCB -) and (iii) COCs which stained blue (BCB + ). BCB + COCs were additionally cultured in standard porcine medium (TCM199) for 44 h. All oocytes were analysed using QT-PCR targeting CDKN1 and CDKN5 mRNA expression. The highest CDKN1 mRNA expression was found in oocytes without BCB staining and IVM (Group I) compared to BCB -and BCB + oocytes, (P < 0.001, P < 0.01, respectively). An increased CDKN5 mRNA level was observed in BCB + oocytes (Group III) compared to oocytes of Group I and Group II (P < 0.01), respectively. The mRNA expression of both genes was always higher in BCB + compared to BCB -oocytes. Based on this study it can be supposed that CDKN1 and CDKN5 are differentially expressed in developmentally distinct porcine oocytes and in a maturation stage-dependent manner. Moreover, CDKN1 may play a role as a molecule which regulates cell cycle arrest and the specific "block of maturation" from MI to MII.

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“…Inhibition of CDK4 activity is considered an attractive strategy for cancer chemotherapy. 53,[200][201][202] Many laboratory studies have indeed shown that chemical inhibitors of CDK4 kinase activity can cause cytostasis, senescence, and even death of cancer cells. 175,200,[203][204][205][206][207][208][209][210][211][212] Moreover, knockdown of CDK4 using shRNA also significantly increases radiation-induced apoptosis of malignant and nonmalignant breast cell lines without significantly altering cell cycle progression or post-irradiation DNA repair.…”

Section: Inhibition Of Cdk4 For Cancer Therapy May Also Have Weaknessesmentioning

confidence: 99%

The other side of the coin: The tumor-suppressive aspect of oncogenes and the oncogenic aspect of tumor-suppressive genes, such as those along the CCND–CDK4/6–RB axis

et al. 2014

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Although cancer-regulatory genes are dichotomized to oncogenes and tumor-suppressor gene s, in reality they can be oncogenic in one situation but tumor-suppressive in another. This dual-function nature, which sometimes hampers our understanding of tumor biology, has several manifestations: (1) Most canonically defined genes have multiple mRNAs, regulatory RNAs, protein isoforms, and posttranslational modifications; (2) Genes may interact at different levels, such as by forming chimeric RNAs or by forming different protein complexes; (3) Increased levels of tumor-suppressive genes in normal cells drive proliferation of cancer progenitor cells in the same organ or tissue by imposing compensatory proliferation pressure, which presents the dual-function nature as a cell-cell interaction. All these manifestations of dual functions can find examples in the genes along the CCND-CDK4/6-RB axis. The dual-function nature also underlies the heterogeneity of cancer cells. Gene-targeting chemotherapies, including that targets CDK4, are effective to some cancer cells but in the meantime may promote growth or progression of some others in the same patient. Redefining "gene" by considering each mRNA, regulatory RNA, protein isoform, and posttranslational modification from the same genomic locus as a "gene" may help in better understanding tumor biology and better selecting targets for different sub-populations of cancer cells in individual patients for personalized therapy.

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Cyclin-Dependent Kinase 4/6 (Cdk4/6) Inhibitors: Perspectives in Cancer Therapy and Imaging

Cited by 30 publications

References 0 publications

Discovery of 8-Cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a Potent Inhibitor of Cyclin-Dependent Kinase 4 (CDK4) and AMPK-Related Kinase 5 (ARK5)

Discovery of 8-Cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a Potent Inhibitor of Cyclin-Dependent Kinase 4 (CDK4) and AMPK-Related Kinase 5 (ARK5)

Expression of cyclin-dependent kinase inhibitors (CDKN1, CDKN5) in developmentally competent and incompetent porcine oocytes

The other side of the coin: The tumor-suppressive aspect of oncogenes and the oncogenic aspect of tumor-suppressive genes, such as those along the CCND–CDK4/6–RB axis

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