NU6140
目录号 : GC34692
A Cdk2 inhibitor
Cas No.:444723-13-1
Sample solution is provided at 25 µL, 10mM.
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- Purity: >99.50%
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NU 6140 is a cyclin-dependent kinase 2 (Cdk2) inhibitor (IC50 = 0.41 μM) that demonstrates 10- to 36-fold selectivity against Cdk2-cyclin A compared to Cdk1-cyclin B, Cdk4-cyclin D, Cdk5-p25, or Cdk7-cyclin H.1 NU 6140 has been found to induce cell-cycle arrest at the G2-M phase and to potentiate the apoptotic effect of paclitaxel in HeLa cells by inhibiting the anti-apoptotic protein, survivin.1
1.Pennati, M., Campbell, A.J., Curto, M., et al.Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140: A possible role for survivin down-regulationMol. Cancer Ther.4(9)1328-1337(2005)
Cas No. | 444723-13-1 | SDF | |
Canonical SMILES | CCN(CC)C(C(C=C1)=CC=C1NC2=NC(OCC3CCCCC3)=C4C(N=CN4)=N2)=O | ||
分子式 | C23H30N6O2 | 分子量 | 422.52 |
溶解度 | DMF: 30 mg/ml,DMSO: 30 mg/ml,Ethanol: 30 mg/ml,Ethanol:PBS (pH 7.2) (1:3): 0.25 mg/ml | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
1 mM | 2.3668 mL | 11.8338 mL | 23.6675 mL |
5 mM | 0.4734 mL | 2.3668 mL | 4.7335 mL |
10 mM | 0.2367 mL | 1.1834 mL | 2.3668 mL |
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Structural and binding studies of cyclin-dependent kinase 2 with NU6140 inhibitor
Chem Biol Drug Des 2021 Nov;98(5):857-868.PMID:34423559DOI:10.1111/cbdd.13941.
Cyclin-dependent kinase 2 (CDK2) is an established target protein for therapeutic intervention in various diseases, including cancer. Reported inhibitors of CDK2 target the ATP-binding pocket to inhibit the kinase activity. Many small molecule CDK2 inhibitors have been discovered, and their crystal structure with CDK2 or CDK2-cyclin A complex has been published. NU6140 is a CDK2 inhibitor with moderate potency and selectivity. Herein, we report the cocrystal structure determination of NU6140 in complex with CDK2 and confirmation of the binding using various biophysical methods. Our data show that NU6140 binds to CDK2 with a Kd of 800 nM as determined by SPR and stabilizes the protein against thermal denaturation (ΔTm -5°C). The cocrystal structure determined in our study shows that NU6140 binds in the ATP-binding pocket as expected for this class of compounds and interacts with Leu83 and Glu81 with regular hydrogen bonds and with Asp145 via water-mediated H-bond. Based on these data, we propose structural modifications of NU6140 to introduce new interactions with CDK2 that can improve its potency while retaining the selectivity.
Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140: a possible role for survivin down-regulation
Mol Cancer Ther 2005 Sep;4(9):1328-37.PMID:16170024DOI:10.1158/1535-7163.MCT-05-0022.
Cyclin-dependent kinases (CDK) play a crucial role in the control of the cell cycle. Aberrations in the control of cell cycle progression occur in the majority of human malignancies; hence, CDKs are promising targets for anticancer therapy. Here, we define the cellular effects of the novel CDK inhibitor NU6140, alone or in association with paclitaxel, with respect to inhibition of cell proliferation and cell cycle progression and induction of apoptosis in HeLa cervical carcinoma cells and in comparison with purvalanol A. Both CDK inhibitors induced a concentration-dependent cell cycle arrest at the G(2)-M phase and an increase in the apoptotic rate, with a concomitant down-regulation of the antiapoptotic protein survivin, a member of the inhibitors of apoptosis protein family. Notably, the addition of NU6140 to paclitaxel-treated cells resulted in markedly increased cytotoxic effect and apoptotic response in comparison with the paclitaxel-purvalanol A combination (86 +/- 11% and 37 +/- 8%, respectively). Similarly, the extent of caspase-9 and caspase-3 activation in paclitaxel-NU6140-treated cells was approximately 4-fold higher than after the paclitaxel-purvalanol A combination. Moreover, an almost complete abrogation of the expression of the active, Thr(34)-phosphorylated form of survivin was observed in cells exposed to the paclitaxel-NU6140 combination. A synergistic effect of the paclitaxel-NU6140 combination, as a consequence of survivin inhibition and increased activation of caspase-9 and caspase-3, was also observed in OAW42/e ovarian cancer line but not in the derived OAW42/Surv subline ectopically expressing survivin. Results from this study indicate that NU6140 significantly potentiates the apoptotic effect of paclitaxel, with inhibition of survivin expression/phosphorylation as the potential mechanism.
Assessment of the Potential of CDK2 Inhibitor NU6140 to Influence the Expression of Pluripotency Markers NANOG, OCT4, and SOX2 in 2102Ep and H9 Cells
Int J Cell Biol 2014;2014:280638.PMID:25477962DOI:10.1155/2014/280638.
As cyclin-dependent kinases (CDKs) regulate cell cycle progression and RNA transcription, CDKs are attractive targets for creating cancer cell treatments. In this study we investigated the effects of the small molecular agent NU6140 (inhibits CDK2 and cyclin A interaction) on human embryonic stem (hES) cells and embryonal carcinoma-derived (hEC) cells via the expression of transcription factors responsible for pluripotency. A multiparameter flow cytometric method was used to follow changes in the expression of NANOG, OCT4, and SOX2 together in single cells. Both hES and hEC cells responded to NU6140 treatment by induced apoptosis and a decreased expression of NANOG, OCT4, and SOX2 in surviving cells. A higher sensitivity to NU6140 application in hES than hEC cells was detected. NU6140 treatment arrested hES and hEC cells in the G2 phase and inhibited entry into the M phase as evidenced by no significant increase in histone 3 phosphorylation. When embryoid bodies (EBs) formed from NU6104 treated hES cells were compared to EBs from untreated hES cells differences in ectodermal, endodermal, and mesodermal lineages were found. The results of this study highlight the importance of CDK2 activity in maintaining pluripotency of hES and hEC cells and in differentiation of hES cells.
Cyclin-dependent kinases regulate apoptosis of intestinal epithelial cells
Apoptosis 2014 Mar;19(3):451-66.PMID:24242917DOI:10.1007/s10495-013-0942-3.
Homeostasis of the gastrointestinal epithelium is dependent upon a balance between cell proliferation and apoptosis. Cyclin-dependent kinases (Cdks) are well known for their role in cell proliferation. Previous studies from our group have shown that polyamine-depletion of intestinal epithelial cells (IEC-6) decreases cyclin-dependent kinase 2 (Cdk2) activity, increases p53 and p21Cip1 protein levels, induces G1 arrest, and protects cells from camptothecin (CPT)-induced apoptosis. Although emerging evidence suggests that members of the Cdk family are involved in the regulation of apoptosis, their roles directing apoptosis of IEC-6 cells are not known. In this study, we report that inhibition of Cdk1, 2, and 9 (with the broad range Cdk inhibitor, AZD5438) in proliferating IEC-6 cells triggered DNA damage, activated p53 signaling, inhibited proliferation, and induced apoptosis. By contrast, inhibition of Cdk2 (with NU6140) increased p53 protein and activity, inhibited proliferation, but had no effect on apoptosis. Notably, AZD5438 sensitized, whereas, NU6140 rescued proliferating IEC-6 cells from CPT-induced apoptosis. However, in colon carcinoma (Caco-2) cells with mutant p53, treatment with either AZD5438 or NU6140 blocked proliferation, albeit more robustly with AZD5438. Both Cdk inhibitors induced apoptosis in Caco-2 cells in a p53-independent manner. In serum starved quiescent IEC-6 cells, both AZD5438 and NU6140 decreased TNF-α/CPT-induced activation of p53 and, consequently, rescued cells from apoptosis, indicating that sustained Cdk activity is required for apoptosis of quiescent cells. Furthermore, AZD5438 partially reversed the protective effect of polyamine depletion whereas NU6140 had no effect. Together, these results demonstrate that Cdks possess opposing roles in the control of apoptosis in quiescent and proliferating cells. In addition, Cdk inhibitors uncouple proliferation from apoptosis in a p53-dependent manner.
How Selective Are Pharmacological Inhibitors of Cell-Cycle-Regulating Cyclin-Dependent Kinases?
J Med Chem 2018 Oct 25;61(20):9105-9120.PMID:30234987DOI:10.1021/acs.jmedchem.8b00049.
Cyclin-dependent kinases (CDKs) are an important and emerging class of drug targets for which many small-molecule inhibitors have been developed. However, there is often insufficient data available on the selectivity of CDK inhibitors (CDKi) to attribute the effects on the presumed target CDK to these inhibitors. Here, we highlight discrepancies between the kinase selectivity of CDKi and the phenotype exhibited; we evaluated 31 CDKi (claimed to target CDK1-4) for activity toward CDKs 1, 2, 4, 5, 7, 9 and for effects on the cell cycle. Our results suggest that most CDKi should be reclassified as pan-selective and should not be used as a tool. In addition, some compounds did not even inhibit CDKs as their primary cellular targets; for example, NU6140 showed potent inhibition of Aurora kinases. We also established an online database of commercially available CDKi for critical evaluation of their utility as molecular probes. Our results should help researchers select the most relevant chemical tools for their specific applications.