| 名稱 | AMG 900 |
| 描述 | AMG 900 is a potent and highly selective pan-Aurora kinases inhibitor for Aurora A/B/C with IC50 of 5 nM/4 nM /1 nM. It is >10-fold selective for Aurora kinases than p38α, Tyk2, JNK2, Met and Tie2. Phase 1. |
| 細(xì)胞實(shí)驗(yàn) | Tumor cells are treated with AMG 900 for 48 hours, washed twice with complete media, and cells are replated at a density of 5000 cells per well in drug-free complete media. Cells are grown until the DMSO control wells are confluent. Cells are stained with crystal violet dye, washed with distilled water, and imaged using a digital scanner.(Only for Reference) |
| 激酶實(shí)驗(yàn) | Enzyme kinase assays: Recombinant GST- or His-tagged aurora-A (TPX2), and aurora-B proteins are expressed using a baculovirus system and purified by affinity chromatography. AMG 900 activity is assessed using a standardized homogenous time-resolved fluorescence (HTRF) assay. Enzyme assays for 24 other kinases (aurora-C, p38α, TYK2, JNK2, JAK3, c-Met, VEGFR2, p38β, TIE-2, ABL (T315I), ERK1, BTK, JNK3, CDK5, PKAα, JNK1, p70S6K, PKBα, MSK1, LCK, SRC, IGFR, JAK2, and c-KIT) are done internally in a similar manner. Concentrations of enzyme, peptide substrate, and ATP in the reaction are optimized depending on the specific activity of the kinase and measured Km values for their corresponding substrates. AMG 900 is evaluated in a kinome competition binding assay (n = 353 unique kinases) by Ambit Biosciences. AMG 900 is initially screened at a single concentration of 1000 nM, and quantitative binding constants (Kd) are determined for each positive hit (< 20 percentage of control). |
| 體外活性 | AMG 900 是一種新型的、與ATP競(jìng)爭(zhēng)的 phthalazinamine 小分子抑制劑，針對(duì)aurora kinases。在HeLa細(xì)胞中，AMG 900 抑制aurora-A和-B的自磷酸化以及histone H3在Ser位點(diǎn)的磷酸化。腫瘤細(xì)胞對(duì)AMG 900處理的主要細(xì)胞反應(yīng)是終止細(xì)胞分裂而不是延長(zhǎng)的有絲分裂停滯，這最終導(dǎo)致細(xì)胞死亡。AMG 900能夠在低納摩爾濃度（約2-3 nM）抑制26種腫瘤細(xì)胞系的增殖，包括對(duì)抗有絲分裂化合物紫杉醇和其他aurora kinase抑制劑（AZD1152、MK-0457和PHA-739358）耐藥的細(xì)胞系。此外，AMG 900 在一株對(duì)AZD1152耐藥且攜帶aurora-B突變（W221L）的HCT116變異細(xì)胞系中也顯示出活性。[1] |
| 體內(nèi)活性 | AMG 900通過(guò)口服給藥方式能以劑量依賴性的方式阻斷組蛋白H3的磷酸化，并顯著抑制HCT116腫瘤異種移植物的生長(zhǎng)。AMG 900在多個(gè)異種移植模型中表現(xiàn)出廣泛的活性，包括代表5種腫瘤類型的3個(gè)多藥物耐藥性移植模型。[1] AMG 900表現(xiàn)出低至中等的清除率和小的分布體積，其終末消除半衰期介于0.6到2.4小時(shí)之間。在禁食的動(dòng)物中，AMG 900具有良好的口服生物利用度，范圍為31%至107%。食物攝入會(huì)影響AMG 900的口服吸收率（大鼠）或吸收程度（狗）。在人體中，穩(wěn)態(tài)時(shí)的清除率和分布體積預(yù)計(jì)分別為27.3 mL/h/kg和93.9 mL/kg。AMG 900在臨床前物種中顯示出可接受的藥代動(dòng)力學(xué)（PK）屬性，并預(yù)計(jì)在人體中具有低清除率。[2] |
| 存儲(chǔ)條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | Ethanol : < 1 mg/mL (insoluble or slightly soluble)
H2O : < 1 mg/mL (insoluble or slightly soluble)
DMSO : 93 mg/mL (184.7 mM)
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| 關(guān)鍵字 | Inhibitor | Aurora Kinase | AMG 900 | inhibit |
| 相關(guān)產(chǎn)品 | (-)-Bornyl acetate | Doramapimod | Deucravacitinib | Gefitinib | Palmatine | Exarafenib | SB 202190 | MW-150 | Ibrutinib | Delgocitinib | Palmatine chloride | Bakuchiol |
| 相關(guān)庫(kù) | 抑制劑庫(kù) | 抗癌活性化合物庫(kù) | 經(jīng)典已知活性庫(kù) | 已知活性化合物庫(kù) | 激酶抑制劑庫(kù) | 高選擇性抑制劑庫(kù) | 抗衰老化合物庫(kù) | 藥物功能重定位化合物庫(kù) | 酪氨酸激酶分子庫(kù) | 抗癌藥物庫(kù) |