MK-5198 - CAS 1010085-13-8
Catalog number: 1010085-13-8
Category: Inhibitor
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Aurora Kinase
MK-5108 is a novel small molecule with potent inhibitory activity against Aurora-A kinase. Although most of the Aurora-kinase inhibitors target both Aurora-A and Aurora-B, MK-5108 specifically inhibited Aurora-A kinase in a panel of protein kinase assays. Inhibition of Aurora-A by MK-5108 in cultured cells induced cell cycle arrest at the G(2)-M phase in flow cytometry analysis. The effect was confirmed by the accumulation of cells with expression of phosphorylated Histone H3 and inhibition of Aurora-A autophosphorylation by immunostaining assays. MK-5108 also induced phosphorylated Histone H3 in skin and xenograft tumor tissues in a nude rat xenograft model. MK-5108 inhibited growth of human tumor cell lines in culture and in different xenograft models. Furthermore, the combination of MK-5108 and docetaxel showed enhanced antitumor activities compared with control and docetaxel alone-treated animals without exacerbating the adverse effects of docetaxel. MK-5108 is currently tested in clinical trials and offers a new therapeutic approach to combat human cancers as a single agent or in combination with existing taxane therapies.
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MK5108; MK-5108; MK 5108; VX689; VX 689; VX-689.
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1.Fluorescent photoaffinity probes for mitotic protein kinase Aurora A.
Lavogina D;Kisand K;Raidaru G;Uri A Bioorg Med Chem Lett. 2015 Aug 15;25(16):3290-4. doi: 10.1016/j.bmcl.2015.05.060. Epub 2015 May 30.
We combined the advantages of the selective inhibitor VX689, the bisubstrate-analogue conjugate approach, and photoreactive amino acids to develop 8 photoaffinity probes for Aurora A. The most efficient compounds possessed one-digit nanomolar KD values in the equilibrium binding assay, inhibited Aurora A at elevated concentrations of ATP in the phosphorylation assay in the presence of TPX2, and formed covalent complexes with the recombinant kinase or Aurora A in HeLa cells upon UV-irradiation. The recognition of the correct target by the probes during formation of the covalent complex in the biochemical assay and in situ was demonstrated by competition experiments using the non-labelled inhibitors VX689 and MLN8237.
2.Co-inhibition of polo-like kinase 1 and Aurora kinases promotes mitotic catastrophe.
Li J;Hong MJ;Chow JP;Man WY;Mak JP;Ma HT;Poon RY Oncotarget. 2015 Apr 20;6(11):9327-40.
Mitosis is choreographed by a number of protein kinases including polo-like kinases and Aurora kinases. As these kinases are frequently dysregulated in cancers, small-molecule inhibitors have been developed for targeted anticancer therapies. Given that PLK1 and Aurora kinases possess both unique functions as well as co-regulate multiple mitotic events, whether pharmacological inhibition of these kinases together can enhance mitotic catastrophe remains an outstanding issue to be determined. Using concentrations of inhibitors that did not induce severe mitotic defects on their own, we found that both the metaphase arrest and mitotic slippage induced by inhibitors targeting Aurora A and Aurora B (MK-5108 and Barasertib respectively) were enhanced by a PLK1 inhibitor (BI 2536). We found that PLK1 is overexpressed in cells from nasopharyngeal carcinoma, a highly invasive cancer with poor prognosis, in comparison to normal nasopharyngeal epithelial cells. Nasopharyngeal carcinoma cells were more sensitive to BI 2536 as a single agent and co-inhibition with Aurora kinases than normal cells. These observations underscore the mechanism and potential benefits of targeting PLK1 and Aurora kinases to induce mitotic catastrophe in cancer cells.
3.Preclinical evaluation of the Aurora kinase inhibitors AMG 900, AZD1152-HQPA, and MK-5108 on SW-872 and 93T449 human liposarcoma cells.
Noronha S;Alt LAC;Scimeca TE;Zarou O;Obrzut J;Zanotti B;Hayward EA;Pillai A;Mathur S;Rojas J;Salamah R;Chandar N;Fay MJ In Vitro Cell Dev Biol Anim. 2018 Jan;54(1):71-84. doi: 10.1007/s11626-017-0208-4. Epub 2017 Dec 1.
Liposarcoma is a malignant soft tissue tumor that originates from adipose tissue and is one of the most frequently diagnosed soft tissue sarcomas in humans. There is great interest in identifying novel chemotherapeutic options for treating liposarcoma based upon molecular alterations in the cancer cells. The Aurora kinases have been identified as promising chemotherapeutic targets based on their altered expression in many human cancers and cellular roles in mitosis and cytokinesis. In this study, we investigated the effects of an Aurora kinase A inhibitor (MK-5108), an Aurora kinase B inhibitor (AZD1152-HQPA), and a pan-Aurora kinase inhibitor (AMG 900) on undifferentiated SW-872 and well-differentiated 93T449 human liposarcoma cells. Treatment of the SW-872 and 93T449 cells with MK-5108 (0-1000 nM), AZD1152-HQPA (0-1000 nM), and AMG 900 (0-1000 nM) for 72 h resulted in a dose-dependent decrease in the total viable cell number. Based upon the EC;50; values, the potency of the three Aurora kinase inhibitors in the SW-872 cells was as follows: AMG 900 (EC;50; = 3.7 nM) > AZD1152-HQPA (EC;50; = 43.4 nM) > MK-5108 (EC;50; = 309.0 nM), while the potency in the 93T449 cells was as follows: AMG 900 (EC;50; = 6.
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CAS 1010085-13-8 MK-5198

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