SNS-314
目录号 : GC25940SNS-314 is a potent and selective inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 9 nM, 31 nM, and 3 nM, respectively. It is less potent to Trk A/B, Flt4, Fms, Axl, c-Raf and DDR2. Phase 1.
Cas No.:1057249-41-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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SNS-314 is a potent and selective inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 9 nM, 31 nM, and 3 nM, respectively. It is less potent to Trk A/B, Flt4, Fms, Axl, c-Raf and DDR2. Phase 1.
In HCT116 colorectal carcinoma cell line, with intact or depleted p53 protein levels, SNS-314 Mesylate shows enhanced efficacy when administered sequentially with other standard chemotherapeutic agents and the most profound synergies are identified for agents that activate the spindle assembly checkpoint, e.g., docetaxel and vincristine. [2] A recent study shows that SNS-314 Mesylate shows potent antiproliferative activity in HCT116 cells and inhibits soft agar colony formation. [3]
The sequential treatment with SNS-314 Mesylate followed by docetaxel 24 hours later produces a significant 72.5% tumor growth inhibition of HCT116 xenografts, while docetaxel and SNS-314 Mesylate as single agents produce no significant inhibition of HCT116 tumor growth. [2] In the HCT116 human colon cancer xenograft model, administration of 50 and 100 mg/kg SNS-314 Mesylate results a dose-dependent inhibition of histone H3 phosphorylation, indicating effective Aurora-B inhibition in vivo. In addition, HCT116 tumors from animals treated with SNS-314 Mesylate exhibits potent and sustained responses including reduction of phosphorylated histone H3 levels, increased caspase-3 and appearance of increased nuclear size. [3]
[1] Oslob JD, et al. Bioorg Med Chem Lett, 2008, 18(17), 4880-4884. [2] VanderPorten EC, et al. Mol Cancer Ther, 2009, 8(4), 930-939. [3] Arbitrario JP, et al. Cancer Chemother Pharmacol, 2010, 65(4), 707-717.
| Cas No. | 1057249-41-8 | SDF | Download SDF |
| 分子式 | C18H15ClN6OS2 | 分子量 | 430.93 |
| 溶解度 | DMSO: 100 mg/mL (232.06 mM);Water: Insoluble;Ethanol: Insoluble | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.3206 mL | 11.6028 mL | 23.2056 mL |
| 5 mM | 0.4641 mL | 2.3206 mL | 4.6411 mL |
| 10 mM | 0.2321 mL | 1.1603 mL | 2.3206 mL |
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2.
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3. 以上所有助溶剂都可在 GlpBio 网站选购。
SNS-314, a pan-Aurora kinase inhibitor, shows potent anti-tumor activity and dosing flexibility in vivo
Cancer Chemother Pharmacol 2010 Mar;65(4):707-17.PMID:19649632DOI:10.1007/s00280-009-1076-8.
Purpose: The Aurora family of serine/threonine kinases (Aurora-A, Aurora-B, and Aurora-C) plays a key role in cells orderly progression through mitosis. Elevated expression levels of Aurora kinases have been detected in a high percentage of melanoma, colon, breast, ovarian, gastric, and pancreatic tumors. We characterized the biological and pharmacological properties of SNS-314, an ATP-competitive, selective, and potent inhibitor of Aurora kinases. Methods: We studied the biochemical potency and selectivity of SNS-314 to inhibit Aurora kinases A, B, and C. The inhibition of cellular proliferation induced by SNS-314 was evaluated in a broad range of tumor cell lines and correlated to inhibition of histone H3 phosphorylation, inhibition of cell-cycle progression, increase in nuclear content and cell size, loss of viability, and induction of apoptosis. The dose and administration schedule of SNS-314 was optimized for in vivo efficacy in mouse xenograft models of human cancer. Results: In the HCT116 human colon cancer xenograft model, administration of 50 and 100 mg/kg SNS-314 led to dose-dependent inhibition of histone H3 phosphorylation for at least 10 h, indicating effective Aurora-B inhibition in vivo. HCT116 tumors from animals treated with SNS-314 showed potent and sustained responses including reduction of phosphorylated histone H3 levels, increased caspase-3 and appearance of increased nuclear size. The compound showed significant tumor growth inhibition in a dose-dependent manner under a variety of dosing schedules including weekly, bi-weekly, and 5 days on/9 days off. Conclusions: SNS-314 is a potent small-molecule inhibitor of Aurora kinases developed as a novel anti-cancer therapeutic agent for the treatment of diverse human malignancies.
The Aurora kinase inhibitor SNS-314 shows broad therapeutic potential with chemotherapeutics and synergy with microtubule-targeted agents in a colon carcinoma model
Mol Cancer Ther 2009 Apr;8(4):930-9.PMID:19372566DOI:10.1158/1535-7163.MCT-08-0754.
Aurora kinases play key roles in regulating centrosome maturation, mitotic spindle formation, and cytokinesis during cell division, and are considered promising drug targets due to their frequent overexpression in a variety of human cancers. SNS-314 is a selective and potent pan Aurora inhibitor currently in a dose escalation phase 1 clinical trial for the treatment of patients with advanced solid tumors. Here, we report the antiproliferative effects of SNS-314 in combination with common chemotherapeutics in cell culture and xenograft models. The HCT116 colorectal carcinoma cell line, with intact or depleted p53 protein levels, was treated with SNS-314 and a cytotoxic chemotherapeutic from a panel comprised of gemcitabine, 5-fluorouracil (5-FU), carboplatin, daunomycin, SN-38 (the active metabolite of irinotecan), docetaxel, and vincristine. Combinations were administered under either concurrent or sequential schedules. SNS-314 has predominantly additive effects when administered concurrently with commonly used anticancer agents. Sequential administration of SNS-314 with chemotherapeutic compounds showed additive antiproliferative effects with carboplatin, gemcitabine, 5-FU, daunomycin, and SN-38, and synergy was observed in combination with gemcitabine, docetaxel, or vincristine. The most profound antiproliferative effects were observed with sequential administration of SNS-314 followed by docetaxel or vincristine. In vivo, SNS-314 potentiated the antitumor activity of docetaxel in xenografts. Both the in vitro synergies observed between SNS-314 and agents that target the mitotic spindle and the potentiation seen with docetaxel in vivo are consistent with a mechanism of action in which Aurora inhibition bypasses the mitotic spindle assembly checkpoint and prevents cytokinesis, augmenting subsequent spindle toxin-mediated mitotic catastrophe and cell death.
Effects of the Aurora kinases pan-inhibitor SNS-314 mesylate on anaplastic thyroid cancer derived cell lines
Clin Ter 2012;163(5):e307-13.PMID:23099978doi
Objectives: Anaplastic thyroid carcinomas (ATC) are highly aggressive tumours unresponsive to any available radio- or chemotherapeutic protocol, with a median survival rate of 4-5 months from the time of diagnosis. We previously demonstrated that ATC are characterized by increased expression of the kinases Aurora-A, -B and -C, involved in the regulation of multiple steps of the mitotic phase. In this study, the in vitro effects of SNS-314 mesylate, a pan-inhibitor of the Aurora kinases, on growth and tumorigenicity of ATC cells were evaluated. Materials and methods: The effects of SNS-314 mesylate were assessed on the ATC derived cell lines CAL-62, 8305C, 8505C and BHT-101 by means of cell proliferation assay, immunofluorescence, cytofluorimetry, time lapse microscopy, and colony formation in soft agar. Results: Treatment of the different ATC cells with SNS-314 mesylate inhibited proliferation in a time- and dose-dependent manner, with IC(50) comprised between 2.6 nM and 26.6 nM. CAL-62 cells exposed for 24 h to SNS-314 mesylate 100 nM evidenced a significant augmentation of the apoptotic index. Time-lapse video-microscopy of CAL-62 cells showed that SNS-314 mesylate prevents the completion of mitosis leading to polyploidy. Western blot experiments demonstrated that the auto-phosphorylation of the Aurora kinases as well as histone H3 phosphorylation in CAL-62 treated cells was inhibited. Finally, the drug inhibited colony formation in soft agar of all cell lines. Conclusions: Our results demonstrated that SNS-314 mesylate is capable to efficiently reduce cell growth and tumorigenicity of different ATC derived cell lines suggesting its potential therapeutic value for ATC treatment.
3D-QSAR and molecular docking studies on derivatives of MK-0457, GSK1070916 and SNS-314 as inhibitors against Aurora B kinase
Int J Mol Sci 2010 Nov 2;11(11):4326-47.PMID:21151441DOI:10.3390/ijms11114326.
Development of anticancer drugs targeting Aurora B, an important member of the serine/threonine kinases family, has been extensively focused on in recent years. In this work, by applying an integrated computational method, including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), homology modeling and molecular docking, we investigated the structural determinants of Aurora B inhibitors based on three different series of derivatives of 108 molecules. The resultant optimum 3D-QSAR models exhibited (q(2) = 0.605, r(2) (pred) = 0.826), (q(2) = 0.52, r(2) (pred) = 0.798) and (q(2) = 0.582, r(2) (pred) = 0.971) for MK-0457, GSK1070916 and SNS-314 classes, respectively, and the 3D contour maps generated from these models were analyzed individually. The contour map analysis for the MK-0457 model revealed the relative importance of steric and electrostatic effects for Aurora B inhibition, whereas, the electronegative groups with hydrogen bond donating capacity showed a great impact on the inhibitory activity for the derivatives of GSK1070916. Additionally, the predictive model of the SNS-314 class revealed the great importance of hydrophobic favorable contour, since hydrophobic favorable substituents added to this region bind to a deep and narrow hydrophobic pocket composed of residues that are hydrophobic in nature and thus enhanced the inhibitory activity. Moreover, based on the docking study, a further comparison of the binding modes was accomplished to identify a set of critical residues that play a key role in stabilizing the drug-target interactions. Overall, the high level of consistency between the 3D contour maps and the topographical features of binding sites led to our identification of several key structural requirements for more potency inhibitors. Taken together, the results will serve as a basis for future drug development of inhibitors against Aurora B kinase for various tumors.
Gateways to clinical trials
Methods Find Exp Clin Pharmacol 2009 Jan-Feb;31(1):47-57.PMID:19357798doi
(-)-Gossypol; Alemtuzumab, Amlodipine, Anakinra, Azacitidine; Bazedoxifene acetate, Belinostat, Bevacizumab, BI-201335, BI-2536, Biphasic insulin aspart, Bortezomib; Cetuximab, CNTO-328, Custirsen sodium; Dacetuzumab; Elacytarabine, Erlotinib hydrochloride, Everolimus, Exenatide; Forodesine hydrochloride, Fostamatinib disodium, Frovatriptan; Ibutamoren mesilate, Imatinib mesylate, IMC-18F1, INCB-18424, Indacaterol, Insulin detemir, Insulin glargine, Insulin glulisine; KW-0761, KW-2449; Lapatinib ditosylate, Liraglutide; MK-2461, Mycophenolic acid sodium salt; Peginterferon alfa-2a, Pemetrexed disodium, Pioglitazone hydrochloride/metformin hydrochloride, Pregabalin; rBCG-30; Satraplatin, SB-743921, Short ragweed pollen allergenic extract, SNS-314, Sorafenib, Sugammadex sodium, Sunitinib malate; Teriparatide; Valsartan/amlodipine besylate, Vinflunine, Vorinostat.