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Research Area
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Description
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Cancer |
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Biological Activity
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Description
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SNS-032 is a novel, potent and selective CDK inhibitor of CDK2, CDK7 and CDK9 with IC50 of 38 nM, 62 nM and 4 nM, respectively. |
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Targets
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CDK2 |
CDK7 |
CDK9 |
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IC50 |
38 nM |
62 nM |
4 nM [1] |
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In Vitro
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SNS-032 has low sensitivity to CDK1 and CDK4 with IC50 of 480 nM and 925 nM, respectively. SNS-032 effectively kills chronic lymphocytic leukemia cells in vitro regardless of prognostic indicators and treatment history. Compared with flavopiridol and roscovitine, SNS-032 is more potent, both in inhibition of RNA synthesis and at induction of apoptosis. SNS-032 activity is readily reversible; removal of SNS-032 reactivates RNA polymerase II, which led to resynthesis of Mcl-1 and cell survival. [1] SNS-032 inhibits three dimensional capillary network formations of endothelial cells. SNS-032 completely prevents U87MG cell–mediated capillary formation of HUVECs. In addition, SNS-032 significantly prevents the production of VEGF in both cell lines, SNS-032 prevents in vitro angiogenesis, and this action is attributable to blocking of VEGF. Preclinical studies have shown that SNS-032 induces cell cycle arrest and apoptosis across multiple cell lines. [2] SNS-032 blocks the cell cycle via inhibition of CDKs 2 and 7, and transcription via inhibition of CDKs 7 and 9. SNS-032 activity is unaffected by human serum. [3]SNS-032 induces a dose-dependent increase in annexin V staining and caspase-3 activation. At the molecular level, SNS-032 induces a marked dephosphorylation of serine 2 and 5 of RNA polymerase (RNA Pol) II and inhibits the expression of CDK2 and CDK9 and dephosphorylated CDK7. [4] |
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In Vivo
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SNS-032 prevents tumor cell-induced VEGF secretion in a tumor coculture model. [2] SNS-032, a new CDK inhibitor, is more selective and less cytotoxic and has been shown to prolong stable disease in solid tumors. [4] |
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Clinical Trials
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SNS-032 currently in phase I clinical trial for chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). |
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Features
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Protocol
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Cell Assay
[2]
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| Cell Lines |
HUVECs and U87MG cells |
| Concentrations |
0–0.5 mM |
| Incubation Time |
24, 48, or 72 hours |
| Methods |
Cell Titer-Glo (CTG) luminescent assay is performed to measure the growth curves of both HUVECs and U87MG cells. U87MG cells and HUVECs (2×103 cells/well) are seeded in a 96-well microplate in a final volume of 100 ml. After 24 hours, cells are treated with various doses of SNS-032 (0–0.5 mM) for 24, 48, or 72 hours. After completion of the treatment, 100 ml of CTG solution is added to each well and incubated for 20 minutes at room temperature in the dark. Lysate (50 ml) is transferred to a 96-well white plate, and luminescence is measured by POLARstar OPTIMA. Percent cell growth is calculated by considering 100% growth at the time of SNS-032 addition. |
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References |
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[1] Chen R, et al. Blood, 2009, 113(19): 4637-45.
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[2] Ali MA, et al. Neoplasia, 2007, 9(5), 370-81.
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[3] Conroy A, et al. Cancer Chemother Pharmacol, 2009, 64(4), 723-32.
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[4] Walsby E, et al. Leukemia, 2011, 25(3), 411-9.
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