SNS-314 Mesylate

SNS-314 is an ATP-competitive and selective inhibitor of aurora kinases with IC50 values of 9 nM, 31 nM and 3 nM against Aurora A, Aurora B and Aurora C, respectively [1 and 2].
Aurora kinases are serine/threonine kinases that regulate mitosis of cells. They are found to be associated with the onset and propagation of cancer and over-expressed in various tumor cell lines such as melanoma, ovarian, colon, pancreatic and breast tumors. Therefore, aurora kinases are being evaluated as potential targets in cancer therapy .As a potent inhibitor of aurora kinase, SNS-314inhibited proliferation in a broad panel of tumor cell lines and showed potent anti-tumor activity in mice bearing HCT116 xenografts. Besides that, a mechanism of its action was found to be inhibiting the phosphorylation of histoneH3 at Ser10 [1 and 2].
In the FRET-based biochemical assay, SNS-314inhibited Aurora A, B and C with IC50 values of 9, 31 and 3 nM, respectively. When tested against a panel of 219 kinases, SNS-314 only inhibited 24 kinases of them by 65% or above. It suggested that SNS-314 was a selective inhibitor of aurora kinase. In cell-based assays, SNS-314 blocked the proliferation of cancer cells with IC50 value in the range from 1.8 nM (A2780) to 24 nM (HT29). In HCT-116 cells, SNS-314 treatment for 16 hours resulted in distinct cell-cycle defects [2].
In human tumor xenograft mouse models, administration of SNS-314 exerted significant anti-tumor activities against xenografts of PC-3, H1299, A2780, MDA-MB-231 and A375 cells. The TGI value achieved between 54% and 91% when the dose was 170 mg/kg. The administration also caused a profound and sustained inhibition of pHH3 which was a substrate of Aurora B [2].
References:
[1] Oslob J D, Romanowski M J, Allen D A, et al. Discovery of a potent and selective aurora kinase inhibitor. Bioorganic & medicinal chemistry letters, 2008, 18(17): 4880-4884.
[2] Arbitrario J P, Belmont B J, Evanchik M J, et al. SNS-314, a pan-Aurora kinase inhibitor, shows potent anti-tumor activity and dosing flexibility in vivo. Cancer chemotherapy and pharmacology, 2010, 65(4): 707-717.

Effects of the Aurora kinases pan-inhibitor SNS-314 mesylate on anaplastic thyroid cancer derived cell lines.[Pubmed:23099978]

Clin Ter. 2012;163(5):e307-13.

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.

SNS-314, a pan-Aurora kinase inhibitor, shows potent anti-tumor activity and dosing flexibility in vivo.[Pubmed:19649632]

Cancer Chemother Pharmacol. 2010 Mar;65(4):707-17.

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.[Pubmed:19372566]

Mol Cancer Ther. 2009 Apr;8(4):930-9.

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.

Discovery of a potent and selective aurora kinase inhibitor.[Pubmed:18678489]

Bioorg Med Chem Lett. 2008 Sep 1;18(17):4880-4.

This communication describes the discovery of a novel series of Aurora kinase inhibitors. Key SAR and critical binding elements are discussed. Some of the more advanced analogues potently inhibit cellular proliferation and induce phenotypes consistent with Aurora kinase inhibition. In particular, compound 21 (SNS-314) is a potent and selective Aurora kinase inhibitor that exhibits significant activity in pre-clinical in vivo tumor models.