生物活性

• 描述In mammalian cells, the aurora kinases (aurora-A, -B, and -C) play essential roles in regulating cell division. The expression of aurora-A and -B is elevated in a variety of human cancers and is associated with high proliferation rates and poor prognosis, making them attractive targets for anticancer therapy^[3]. AMG 900 is a potent and highly selective pan-Aurora kinases inhibitor with IC₅₀ values of 5 nM, 4 nM and 1 nM for Aurora A, B and C, respectively. In tumor cells, AMG 900 inhibited autophosphorylation of aurora-A and -B as well as phosphorylation of histone H3 on Ser(10), a proximal substrate of aurora-B. AMG 900 inhibited the proliferation of 26 tumor cell lines, including cell lines resistant to the antimitotic drug paclitaxel and to other aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations. Furthermore, AMG 900 was active in an AZD1152-resistant HCT116 variant cell line that harbors an aurora-B mutation (W221L)^[3]. Oral administration of AMG 900 blocked the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. Importantly, AMG 900 was broadly active in multiple xenograft models, including 3 multidrug-resistant xenograft models, representing 5 tumor types^[3].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00858377	Advanced Malignancy ... more >> Advanced Solid Tumors Cancer Solid Tumors Tumors Collapse <<	Phase 1	Active, not recruiting	May 1, 2019	United States, Arizona ... more >> Research Site Tucson, Arizona, United States, 85724 United States, California Research Site Los Angeles, California, United States, 90095 United States, Maryland Research Site Baltimore, Maryland, United States, 21231 United States, Nevada Research Site Las Vegas, Nevada, United States, 89148 United States, New Mexico Research Site Albuquerque, New Mexico, United States, 87131 Australia, South Australia Research Site Kurralta Park, South Australia, Australia, 5037 Australia, Victoria Research Site Bentleigh East, Victoria, Australia, 3165 Research Site Parkville, Victoria, Australia, 3050 Collapse <<
  NCT01380756	Cancer Hemato... more >>logic Malignancies Leukemia Myeloid Leukemia Collapse <<	Phase 1	Completed	-	United States, New York ... more >> Research Site Stony Brook, New York, United States, 11794 United States, Ohio Research Site Cleveland, Ohio, United States, 44195 United States, Texas Research Site Houston, Texas, United States, 77030 Collapse <<

• 参考文献

• [1] Huang L, Be X, et al. In vitro and in vivo pharmacokinetic characterizations of AMG 900, an orally bioavailable small molecule inhibitor of aurora kinases. Xenobiotica. 2011 May;41(5):400-8.

  [2] Payton M, Bush TL, et al. Preclinical evaluation of AMG 900, a novel potent and highly selective pan-aurora kinase inhibitor with activity in taxane-resistant tumor cell lines. Cancer Res. 2010 Dec 1;70(23):9846-54.

  [3] Payton M, Bush TL, Chung G, Ziegler B, Eden P, McElroy P, Ross S, Cee VJ, Deak HL, Hodous BL, Nguyen HN, Olivieri PR, Romero K, Schenkel LB, Bak A, Stanton M, Dussault I, Patel VF, Geuns-Meyer S, Radinsky R, Kendall RL. Preclinical evaluation of AMG 900, a novel potent and highly selective pan-aurora kinase inhibitor with activity in taxane-resistant tumor cell lines. Cancer Res. 2010 Dec 1;70(23):9846-54. doi: 10.1158/0008-5472.CAN-10-3001. Epub 2010 Oct 8. PMID: 20935223.