Discovery of <i>N</i>-Phenyl-4-(thiazol-5-yl)pyrimidin-2-amine Aurora Kinase Inhibitors

Wang, Shudong; Midgley, Carol A.; Scaerou, Frederic; Grabarek, Joanna B.; Griffiths, G.; Jackson, Wayne; Kontopidis, George; McClue, Steven J.; McInnes, Campbell; Meades, Christopher; Mezna, Mokdad; Plater, A.; Stuart, Iain; Thomas, Mark; Wood, Graham R.; Clarke, Rosemary G.; Blake, David G.; Zheleva, Daniella; Lane, David P.; Jackson, Robert; Glover, David M.; Fischer, Peter M.

doi:10.1021/jm901913s

Cited by 90 publications

(54 citation statements)

References 74 publications

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“…Our interest in the development of kinase inhibitors has resulted in a number of clinical and pre-clinical drug candidates [21][22][23][24][25][26]. We have now discovered another novel class of 2,4,5-trisubstituted pyrimidine CDK inhibitors.…”

Section: Introductionmentioning

confidence: 99%

In vitro antitumor mechanism of a novel cyclin-dependent kinase inhibitor CDKI-83

et al. 2011

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Cancer is regarded as a proliferative disorder. Inhibition of cyclin-dependent kinases (CDKs), which are the key regulators of the cell-cycle and RNA transcription, represents an attractive strategy for cancer therapy. In this study, we report the cellular mechanistic investigation of CDKI-83, a K (i)-nanomolar CDK9 inhibitor. The compound shows effective anti-proliferative activity in human tumour cell lines with GI(50) <1 μM, and is capable of inducing apoptosis in A2780 human ovarian cancer cells as determined by the activated caspase-3, Annexin V/PI double staining and accumulated cells at the sub-G1 phase of cell-cycle. While A2780 cells were arrested in G(2)/M phase with CDKI-83 treatment, phosphorylation at Thr(320) of PP1α was significantly reduced, indicating CDK1 inhibition. Importantly, this compound reduced phosphorylation at Ser-2 of RNA polymerase II (RNAPII) by inhibiting cellular CDK9 activity, and down-regulated Mcl-1 and Bcl-2. These results suggest that combined inhibition of CDK9 and CDK1 may result in the effective induction of apoptosis and CDKI-83 has the potential to be developed as an anti-cancer agent.

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Section: Introductionmentioning

confidence: 99%

In vitro antitumor mechanism of a novel cyclin-dependent kinase inhibitor CDKI-83

et al. 2011

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“…N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amine derivatives (Fig. 10) [130], with a similar structure to Dasatinib, have been described as potent aurora kinase inhibitors. However, they were not active against serine/threonine protein kinases A, B, and C (PKA, Akt/PKB, PKC) extracellular signal-regulated kinase-2 (ERK2).…”

Section: Thiazole Derivativesmentioning

confidence: 99%

Kinase Regulation by Sulfur and Selenium Containing Compounds

Sanmartín

Plano²,

Font³

et al. 2011

CCDT

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Kinases are enzymes that are involved in a wide-range of cellular targets such as cell proliferation, metabolism, survival and apoptosis. Aberrations in the activity of the kinases have been linked to many human diseases such as diabetes, inflammation and cancer. The discovery of more than 518 kinases encoded by the human genome has spurred the development of rapid screening techniques for potential drugs against these enzymes and these have been identified as interesting targets for medicinal chemistry programs, especially in cancer therapy. On the other hand, sulfur and selenium have been increasingly recognized as essential elements in biology and medicine. Converging data from epidemiological and clinical studies have highlighted these elements as effective chemopreventive agents, particularly against various types of cancer (prostate, lung, breast, leukemia, colon, skin, lymphome, thyroid, pancreas, liver). These elements act through a wide range of potential mechanisms where one identified signal pathway event is kinase modulation, which is common for the two elements and emerges as a valid target. The kinases modulated by sulfur and selenium derivatives include MAP, ERK, JNK, Akt, Cdc2, Cyclin B1 and Cdc25c amongst others. Although both of the elements in question are in the same group in the periodic table and have similar biochemistries, there are relevant differences related to redox potentials, stabilities, oxidation states and anticancer activity. Literature data suggest that the replacement of sulfur by selenium in established cancer chemopreventive agents results in more effective chemopreventive analogs. In view of the multi-target kinase mechanisms in preventing cellular transformation, as well as the differences and similarities between them, in this review we focus on the development of new structures that contain selenium and/or sulfur and discuss our understanding of the regulation of antitumoral effects with emphasis on kinase modulation activity and its implications in cancer.

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“…In this paper, we considered the compound CYC116 ( [19,20]). It has previously been shown that CYC116 inhibits both AK-A and AK-B and it is thought that its main cite of action is the spindle assembly checkpoint.…”

Section: Modelling the Dynamic Effects Of Drug Dose On Multi-cellularmentioning

confidence: 99%

An integrated pharmacokinetic–pharmacodynamic model for an Aurora kinase inhibitor

Kamei

Jackson

Zheleva

et al. 2010

J Pharmacokinet Pharmacodyn

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The spindle assembly checkpoint is a cell cycle surveillance mechanism that ensures the proper separation of chromosomes prior to cell division at mitosis. Aurora kinases play critical roles in mitotic progression and hence small-molecule inhibitors of Aurora kinases have been developed as a new class of potential anticancer drugs. In this paper we present for the first time an integrated pharmacokinetic-pharmacodynamic model of the functional effects of CYC116 (a known inhibitor of Aurora kinases A and B) on the spindle assembly checkpoint. We use the model to simulate two common experimental systems: cell culture and p.o. dosing of mice and present predictions of the effects of CYC116 for a range of doses and drug scheduling regimes. The model reveals that a critical peak drug concentration is required to cause aberrant kinetochore-microtubule attachments. The model also predicts that provided this threshold concentration is exceeded, a high total oral dose causes a high number of aberrant attachments within any given damaged cell. However, the proportion of cells which enter anaphase with aberrant attachments is associated with the total length of time for which the plasma concentration is maintained above the threshold. Moreover, our model reveals that the length of prometaphase/metaphase is a nonlinear function of drug dose and this time period can be extended or shortened. Finally, a strong saturation effect on CYC116 efficacy is predicted by the model. We discuss how these predictions may have implications for further drug trials using CYC116 and other similar AK inhibitors.

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Discovery of N-Phenyl-4-(thiazol-5-yl)pyrimidin-2-amine Aurora Kinase Inhibitors

Cited by 90 publications

References 74 publications

In vitro antitumor mechanism of a novel cyclin-dependent kinase inhibitor CDKI-83

In vitro antitumor mechanism of a novel cyclin-dependent kinase inhibitor CDKI-83

Kinase Regulation by Sulfur and Selenium Containing Compounds

An integrated pharmacokinetic–pharmacodynamic model for an Aurora kinase inhibitor

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