| 名稱 | TAK-659 hydrochloride |
| 描述 | TAK-659 hydrochloride (TAK-659) is a potent and selective inhibitor of spleen tyrosine kinase (SYK) with an IC50 value of 3.2 nM. It is selective against most other kinases, but potent toward both SYK and FLT3. |
| 細胞實驗 | Cell lines: FLT3-dependent cell lines (MV4-11 and MOLM-13)Cells are maintained at 37°C in a humidified atmosphere containing 5-8% CO2. In a panel of hematological and solid tumor cell lines, inhibition of cell viability is determined using the soluble tetrazolium salt, MTS. Cells are seeded in 96-well tissue culture plates and are incubated at 37°C/5% CO2 for 24 hours prior to addition of compounds or DMSO vehicle. After 72 or 96 hours of incubation with compounds, MTS conversion by metabolically active cells is determined by measuring the OD490 nm of the wells using a Thermomax microplate reader. To generate concentration-response curves, cells are treated in duplicate with a range of serial compound dilutions. Prior to addition to cells, compound dilutions are prepared in DMSO. Equal amounts of DMSO are added to cells (final concentration is 0.5%). After background correction and normalization against DMSO-treated cells, EC50 values are calculated by curve-fitting these cell viability results using nonlinear regression analysis. |
| 激酶實驗 | Kinases are prepared in Base Reaction Buffer (20 mM Hepes pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg/mL BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO) and substrate is added with 1.5 mM CaCl2, 16 μg/mL Calmodulin, and 2 mM MnCl2. Varying concentrations of SAR-20347 in DMSO are added to the kinase reaction along with 10 μM 33P-ATP (activity 0.01 μCi/μL final) for IC50 determination[1]. |
| 動物實驗 | Animal Models: Athymic nude mice. Formulation: 0.5% carboxymethylcellulose (CMC). Dosages: 10,30,60 mg/kg QD. Administration: by oral gavage |
| 體外活性 | 在廣泛的激酶檢測中，TAK-659對SYK和FLT-3的選擇性超過290種其他蛋白激酶50倍以上。TAK-659的處理抑制了初級CLL細胞和Burkitt's淋巴瘤細胞共培養(yǎng)中的Syk激活和BCR信號。在懸浮培養(yǎng)的初級CLL細胞中，TAK-659處理后，隨著劑量增加，BCR刺激后SykTyr525、Btk、NFκB、ERK1/2和STAT3的磷酸化水平降低。TAK-659抑制Syk可誘導(dǎo)CLL細胞凋亡，并消除BCR和共培養(yǎng)衍生的存活信號。TAK-659抑制初級CLL細胞向BMSC、CXCL12和CXCL13的趨化性，并消除微環(huán)境誘導(dǎo)的化學(xué)抗性。TAK-659不抑制患有CLL的患者初級T細胞中的TCR信號和T細胞激活的分子特征。在細胞增殖測定中，TAK-659顯示對依賴SYK的細胞系（OCI-LY10）有抑制作用；而對含有影響SYK活性突變的B細胞淋巴瘤敏感，對黏附的初級或固體腫瘤細胞系則無細胞毒性。在細胞活性測定中，TAK-659對FLT3-ITD依賴的細胞系（MV4-11和MOLM-13）敏感，但WT FLT3的RS4-11（ALL細胞系）和RA1（Burkitt's淋巴瘤細胞系）對TAK-659不敏感。在培養(yǎng)的人類腫瘤細胞中，TAK-659強效地抑制了血液來源的細胞系增長，對敏感細胞系統(tǒng)（例如，彌散性大B細胞淋巴瘤和AML）的半最大響應(yīng)濃度（EC50）范圍從11到775 nM。 |
| 體內(nèi)活性 | 在FLT3依賴的MV4-11異種移植模型中，TAK-659在每天60 mg/kg的劑量下，經(jīng)過20天的用藥后顯示出腫瘤退化。初步的血漿和尿液藥代動力學(xué)數(shù)據(jù)表明，TAK-659被迅速吸收(中位Tmax 2-3小時)，在穩(wěn)態(tài)暴露度中表現(xiàn)出中等的變異性(DN-AUCtau的CV為40-50%)，平均峰谷比率為3.2–4.2，且在連續(xù)每日給藥15天后平均積累量為2.1-至2.6倍。未改變藥物的腎臟清除率(CLr)占表觀口服清除率的30–34%，這表明CLr對TAK-659系統(tǒng)清除率的貢獻≥30–34%。TAK-659在體內(nèi)阻斷了針對IgD（免疫球蛋白D抗體）激活的小鼠外周B細胞中CD86表達。 |
| 存儲條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | DMSO : 1 mg/mL, Sonication is recommended.
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| 關(guān)鍵字 | Spleen | Inhibitor | Spleen tyrosine kinase | Cluster of differentiation antigen 135 | inhibit | CLL | related | tyrosine | kinase | FLT3 | TAK659 | Fms like tyrosine kinase 3 | TAK659 Hydrochloride | CD135 | TAK 659 hydrochloride | TAK659 hydrochloride | TAK 659 | fms | Syk | TAK-659 Hydrochloride | TAK 659 Hydrochloride |
| 相關(guān)產(chǎn)品 | Tofacitinib Citrate | Gefitinib | Gilteritinib | Ribociclib | Axitinib | ANTHRAQUINONE-2-CARBOXYLIC ACID | Regorafenib | Pazopanib | Nintedanib | Sorafenib | Regorafenib monohydrate | Ruxolitinib phosphate |
| 相關(guān)庫 | 抑制劑庫 | 抗癌活性化合物庫 | 經(jīng)典已知活性庫 | 已知活性化合物庫 | 激酶抑制劑庫 | 抗衰老化合物庫 | 膜蛋白靶向化合物庫 | 藥物功能重定位化合物庫 | 抗癌臨床化合物庫 | 抗癌藥物庫 |