945595-80-2
中文名稱
AMG 900
英文名稱
AMG 900
CAS
945595-80-2
分子式
C28H21N7OS
分子量
503.59
MOL 文件
945595-80-2.mol
更新日期
2024/10/09 14:16:49
945595-80-2 結(jié)構(gòu)式
基本信息
中文別名
廣譜AURORA激酶抑制劑(AMG 900)N-[4-[[3-(2-氨基-4-嘧啶基)-2-吡啶基]氧基]苯基]-4-(4-甲基-2-噻吩基)-1-酞嗪胺
英文別名
AMG 900AMG-900
AMG900
AMG 900 USP/EP/BP
N-(4-((3-(2-Aminopyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1
N-[4-[[3-(2-Amino-4-pyrimidinyl)-2-pyridinyl]oxy]phenyl]-4-(4-methyl-2-thienyl)-1-phthalazinamine
1-Phthalazinamine, N-[4-[[3-(2-amino-4-pyrimidinyl)-2-pyridinyl]oxy]phenyl]-4-(4-methyl-2-thienyl)-
N-[4-[[3-(2-Amino-4-pyrimidinyl)-2-pyridinyl]oxy]phenyl]-4-(4-methyl-2-thienyl)-1-phthalazinamine AMG 900
所屬類別
生物化工：Aurora Kinase 抑制劑物理化學(xué)性質(zhì)
沸點(diǎn)778.7±70.0 °C(Predicted)
密度1.380
儲(chǔ)存條件Keep in dark place,Sealed in dry,2-8°C
溶解度≥25.2 mg/mL in DMSO; insoluble in H2O; insoluble in EtOH
酸度系數(shù)(pKa)4.79±0.30(Predicted)
形態(tài)固體
顏色Light yellow to yellow
常見(jiàn)問(wèn)題列表
生物活性
AMG-900是一種有效的，高選擇性的pan-Aurora kinases抑制劑，作用于Aurora A/B/C，IC50為5 nM/4 nM/1 nM，作用于Aurora激酶比作用于p38α， Tyk2， JNK2， Met和Tie2選擇性高10倍以上。Phase 1。體外研究
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).體內(nèi)研究
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.靶點(diǎn)
| 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 |
體外研究
MG900是一種新型ATP競(jìng)爭(zhēng)性氨基酞嗪小分子aurora激酶抑制劑。在HeLa細(xì)胞中，AMG 900抑制aurora-A和-B自身磷酸化，并抑制一種aurora-B的近端底物，Ser上組蛋白H3的磷酸化。腫瘤細(xì)胞對(duì)AMG 900治療的主要細(xì)胞應(yīng)答反應(yīng)使細(xì)胞分裂中止，而不延長(zhǎng)有絲分裂停滯期，這最終會(huì)導(dǎo)致細(xì)胞死亡。AMG 900在低納摩爾濃度下(大約2-3 nM)，抑制26腫瘤細(xì)胞系增殖，包括耐抗有絲分裂藥細(xì)胞系和耐其他aurora激酶抑制劑(AZD1152，MK-0457，和PHA-739358)的細(xì)胞系。此外，AMG 900對(duì)AZD1152耐藥的含有aurora-B突變體(W221L)的HCT116變異細(xì)胞系具有活性。
體內(nèi)研究
AMG 900口服給藥劑量依賴性阻斷組蛋白H3的磷酸化，并顯著抑制HCT116腫瘤異種移植物的生長(zhǎng)。AMG 900在多種異種移植模型中廣泛有效，包括3種多重耐藥異種移植模型，代表了5種腫瘤類型。 AMG 900表現(xiàn)出較低到適度的清除率和較小的體積分布容積。它的末端清除半衰期范圍為0.6到2.4小時(shí)。AMG 900在禁食動(dòng)物體內(nèi)能夠被良好吸收，口服生物利用度為31%到107%。食物攝取會(huì)影響AMG 900口服吸收的速率(大鼠)和程度(狗)。在人體內(nèi)，穩(wěn)態(tài)期的清除率和體積分布容積預(yù)計(jì)分別為27.3 mL/h/kg和93.9 mL/kg。AMG 900在臨床前物種體內(nèi)表現(xiàn)出耐受的PK性能，估計(jì)在人體內(nèi)具有低清除率。