945595-80-2

AMG-900是一种有效的，高选择性的pan-Aurora kinases抑制剂，作用于Aurora A/B/C，IC50为5 nM/4 nM/1 nM，作用于Aurora激酶比作用于p38α， Tyk2， JNK2， Met和Tie2选择性高10倍以上。Phase 1。

AMG 900 is a novel class of ATP-competitive phthalazinamine small molecule inhibitors of aurora kinases. In HeLa cells, AMG 900 inhibits autophosphorylation of aurora-A and -B as well as phosphorylation of histone H3 on Ser, a proximal substrate of aurora-B. The predominant cellular response of tumor cells to AMG 900 treatment is aborted cell division without a prolonged mitotic arrest, which ultimately results in cell death. AMG 900 inhibits 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 (about 2- 3 nM). Furthermore, AMG 900 is active in an AZD1152-resistant HCT116 variant cell line that harbors an aurora-B mutation (W221L).

Oral administration of AMG 900 blocks the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. AMG 900 is broadly active in multiple xenograft models, including 3 multidrugresistant xenograft models, representing 5 tumor types. AMG 900 exhibits a low-to-moderate clearance and a small volume of distribution. Its terminal elimination half-life ranged from 0.6 to 2.4 hours. AMG 900 is well-absorbed in fasted animals with an oral bioavailability of 31% to 107%. Food intake has an effect on rate (rats) or extent (dogs) of AMG 900 oral absorption. The clearance and volume of distribution at steady state in humans are predicted to be 27.3 mL/h/kg and 93.9 mL/kg, respectively. AMG 900 exhibits acceptable PK properties in preclinical species and is predicted to have low clearance in humans.

Target	Value
Aurora C (Cell-free assay)	1 nM
Aurora B (Cell-free assay)	4 nM
Aurora A (Cell-free assay)	5 nM
p38α (Cell-free assay)	53 nM

MG900是一种新型ATP竞争性氨基酞嗪小分子aurora激酶抑制剂。在HeLa细胞中，AMG 900抑制aurora-A和-B自身磷酸化，并抑制一种aurora-B的近端底物，Ser上组蛋白H3的磷酸化。肿瘤细胞对AMG 900治疗的主要细胞应答反应使细胞分裂中止，而不延长有丝分裂停滞期，这最终会导致细胞死亡。AMG 900在低纳摩尔浓度下(大约2-3 nM)，抑制26肿瘤细胞系增殖，包括耐抗有丝分裂药细胞系和耐其他aurora激酶抑制剂(AZD1152，MK-0457，和PHA-739358)的细胞系。此外，AMG 900对AZD1152耐药的含有aurora-B突变体(W221L)的HCT116变异细胞系具有活性。

AMG 900口服给药剂量依赖性阻断组蛋白H3的磷酸化，并显著抑制HCT116肿瘤异种移植物的生长。AMG 900在多种异种移植模型中广泛有效，包括3种多重耐药异种移植模型，代表了5种肿瘤类型。 AMG 900表现出较低到适度的清除率和较小的体积分布容积。它的末端清除半衰期范围为0.6到2.4小时。AMG 900在禁食动物体内能够被良好吸收，口服生物利用度为31%到107%。食物摄取会影响AMG 900口服吸收的速率(大鼠)和程度(狗)。在人体内，稳态期的清除率和体积分布容积预计分别为27.3 mL/h/kg和93.9 mL/kg。AMG 900在临床前物种体内表现出耐受的PK性能，估计在人体内具有低清除率。