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          產品搜索:

          手機:18001401806;18915562593

          電話: 0517-86993111;0512-62729923

          傳真: 0512-62729923

          聯系人: 賈經理;胡總

          郵編: 215000

          地址: 江蘇省蘇州市工業園區仁愛路150號C316室

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          Chinese Name

          中文名


          恩替諾特

          English Name

          英文名


          Pyridin-3-ylmethyl 4-(2-aminophenylcarbamoyl)benzylcarbamate

          Alias

          別名


          [[4-[[(2-aminophenyl)amino]carbonyl]phenyl]methyl]- Carbamic acid 3-pyridinylmethyl ester; Entinostat; MS27-275; MS 275; MS 275-27; SNDX 275


          CAS NO.


          209783-80-2

          Formula

          分子式


          C21H20N4O3

          M.W.

          分子量


          376.41

          Class

          分類


          原料藥



          MS-275 is an inhibitor of HDAC (histone deacetylase) that preferentially inhibits HDAC1 (IC50 = 300 nM) over HDAC3 (IC50 = 8 μM). However, MS-275 does not inhibit HDAC8 (IC50 > 100 μM). MS-275 induces cyclin-dependent kinase inhibitor 1A (p21/CIP1/WAF1), slowing cell growth, differentiation, and tumor development in vivo. Recent studies suggest that MS-275 may be particularly useful as an antineoplastic agent when combined with other drugs, like adriamycin, inhibitors of poly (ADP-ribose) polymerase (PARP), or inhibitors of heat shock protein 90 (Hsp90).
          產品描述 MS-275抑制HDACs,作用于HDAC1和HDAC3時,IC50分別為0.51 μM和1.7 μM。
          靶點 HDAC1 HDAC3 
          IC50 0.51 μM 1.7 μM [2] 
          體外研究 MS-275通過作用于2′-氨基而抑制HDACs。MS-275作用于 K562細胞,誘導 p21WAF1/CIP1和凝溶膠蛋白的累積。MS-275作用于A2780細胞,可以降低S期細胞,提高G1期細胞。 MS-275通過抑制HAD而抑制人類腫瘤細胞系,包括 A2780, Calu-3, HL-60, K562, St-4, HT-29, KB-3-1, Capan-1, 4-1St和 HCT-15細胞增殖, IC50 為41.5 nM到4.71 μM。[1]MS-275抑制HDACs,作用于HDAC1和 HDAC3時IC50 分別為0.51 μM和1.7 μM。而對其他的HDACs沒有抑制效果,如HDAC4, 6, 8和10。[2]MS-275有效抑制人類白血病和淋巴癌細胞,包括U937, HL-60, K562, 和Jurkat。MS-275可以誘導U937細胞p21CIP1/WAF1 調節的生長和變異Marker (CD11b)的表達。MS-275降低cyclin D1和抗凋亡蛋白Mcl-1與XIAP的表達。[3]
          體內研究 MS-275按49 mg/kg劑量作用于除了HCT-15的人類移植瘤都顯示出強抗癌活性。[1]MS-275促進惡性實體瘤和惡性血液病的治療可能性,及生理和畸變基因表達的調節。MS-275和IL-2聯用,作用于腎細胞癌顯示出強抗癌活性,因為降低調節性T細胞和增強脾細胞的表達。臨床實驗 MS-275和5-氮雜胞苷聯用用于治療周期性非小細胞肺癌目前處于I/II期臨床實驗階段。
          特征 
          推薦的實驗操作
          激酶實驗:  
          標準HDAC實驗 用HDAC buffer按1:6稀釋鼠肝內的酶。重組人類HDACs按1:4稀釋在HDAC buffer中。用于標準HDAC實驗,60 μl HDAC buffer和10 μl 稀釋的酶溶液在30oC混合。在HDAC buffer中加入30 μl基底液開始HDAC反應,隨后在30oC下溫育30分鐘。加入100 μl胰蛋白酶溶液終止反應,胰蛋白酶溶液由溶于50 mM Tris-HCl(pH 為8.0)的10 mg/ml 胰蛋白酶, 100 mM NaCl,及 2 μM TSA組成。30oC下溫育20分鐘, 通過測定460納米(λex = 390 nm)處的熒光監測AMC的釋放。使用釋放的AMC校準熒光強度 。用于標準時間過程實驗,在初始100 μl HDAC 反應中加入20 pmol 基底物。2-50 pmol 基底物的酶法分析產物獲得熒光AMC,通過測量這種熒光AMC來測定 Km值和 Vmax值。使用Hanes 圖分析實驗數據。記錄的AMC信號是針對沒有酶而有buffer和基底物的空白區。
          細胞試驗: [2]
          細胞系 A2780, Calu-3, HL-60, K562, St-4, HT-29, KB-3-1, Capan-1, 4-1St和HCT-15細胞
          濃度 10 μM 左右
          處理時間 3天
          方法 5×103個腫瘤細胞接種到96孔板上,加入梯度濃度MS-275培養三天。細胞用0.1 mg/mL中性紅在CO2反應器中染色1小時,測定中性紅與50 μL乙醇和150 μL 0.1 M Na2HPO4溶解后的OD540,測定IC50值。
          動物實驗:  
          動物模型 側腹皮下注射A2780, HT-29, HTC-15, KB-3-1, 4-1St, St-4, Capan-1和Calu-3細胞的裸鼠
          配制 溶于0.05 N HCl, 0.1% Tween-80
          劑量 12.3, 24.5和49 mg/kg
          給藥處理 每天口服處理一次,每周進行5天,持續4周。
          溶解性 (25°C)
          ? DMSO 75 mg/mL
          ? 水 <1 mg/mL
          ? 乙醇 <1 mg/mL
          穩定性 2年 -20°C粉狀
          2周4°C溶于DMSO
          6月-80°C溶于DMSO

          1.Biochemical and Biophysical Research Communications, 414 (2011) 25–30. 
          2.Breast Cancer Res Treat , 2010, 131(3), 777-789. 
          3.Sci Signal, 2010, 3, ra80. 
          4.Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. [Bantscheff M, et al. Nat Biotechnol 2011;29(3), 255-265] PubMed: 21258344
          5.Role of checkpoint kinase 1 (Chk1) in the mechanisms of resistance to histone deacetylase inhibitors. [Lee JH, et al. Proc Natl Acad Sci U S A 2011;108(49):19629-34] PubMed: 22106282
          6.Selective class I histone deacetylase inhibition suppresses hypoxia-induced cardiopulmonary remodeling through an antiproliferative mechanism. [Cavasin MA, et al. Circ Res 2012;110(5):739-48] PubMed: 22282194
          7.Schizophrenia is associated with dysregulation of a Cdk5 activator that regulates synaptic protein expression and cognition. [Engmann O, et al. Brain 2011;134(Pt 8):2408-21] PubMed: 21772061
          8.Histone deacetylase inhibitors preserve white matter structure and function during ischemia by conserving ATP and reducing excitotoxicity. [Baltan S, et al. J Neurosci 2011;31(11):3990-9] PubMed: 21411642
          9.DNMT1 stability is regulated by proteins coordinating deubiquitination and acetylation-driven ubiquitination. [Du Z, et al. Sci Signal 2010;3(146), ra80] PubMed: 21045206
          10.IL-10 Regulates Il12b Expression via Histone Deacetylation: Implications for Intestinal Macrophage Homeostasis. [Kobayashi T, et al. J Immunol 2012;189(4):1792-9] PubMed: 22786766
          11.RSK2Ser227 at N-terminal kinase domain is a potential therapeutic target for multiple myeloma. [Shimura Y, et al. Mol Cancer Ther 2012;11(12):2600-9] PubMed: 23012246
          12.Inhibitors of histone demethylation and histone deacetylation cooperate in regulating gene expression and inhibiting growth in human breast cancer cells. [Huang Y, et al. Breast Cancer Res Treat 2012;131(3), 777-789] PubMed: 21452019
          13.Histone Deacetylase Inhibitors (HDACis) That Release the Positive Transcription Elongation Factor b (P-TEFb) from Its Inhibitory Complex Also Activate HIV Transcription. [Bartholomeeusen K, et al. J Biol Chem 2013;288(20), 14400-14407] PubMed: 23539624
          14.Histone Deacetylase Inhibitors (HDACis) That Release the Positive Transcription Elongation Factor b (P-TEFb) from Its Inhibitory Complex Also Activate HIV Transcription. [Bartholomeeusen K, et al. J Biol Chem 2013;288(20), 14400-7] PubMed: 23539624
          15.Histone deacetylase inhibitors downregulate checkpoint kinase 1 expression to induce cell death in non-small cell lung cancer cells. [Brazelle W, et al. PLoS One 2010;5(12), e14335] PubMed: 21179472
          16.Enhancement of vaccinia virus based oncolysis with histone deacetylase inhibitors. [MacTavish H, et al. PLoS One 2010;5(12), e14462] PubMed: 21283510
          17.Inhibition of class II histone deacetylases in the spinal cord attenuates inflammatory hyperalgesia. [Bai G, et al. Mol Pain 2010;6, 51] PubMed: 20822541
          18.Histone deacetylase inhibitors preserve function in aging axons. [Baltan S, et al. J Neurochem 2012;123 Suppl 2:108-15] PubMed: 23050648
          19.Epithelial to mesenchymal transition in an epidermal growth factor receptor-mutant lung cancer cell line with acquired resistance to erlotinib. [Suda K, et al. J Thorac Oncol 2011;6(7):1152-61] PubMed: 21597390
          20.Sca-1 is an early-response target of histone deacetylase inhibitors and marks hematopoietic cells with enhanced function. [Walasek MA, et al. Exp Hematol 2013;41(1):113-23.e2] PubMed: 22989761
          21.Differential regulation of theSMN2 gene by individual HDAC proteins. [Evans MC, et al. Biochem Biophys Res Commun 2011;414(1):25-30]  PubMed: 21925145
          22.Histone Deacetylase Activity Selectively Regulates Notch-Mediated Smooth Muscle Differentiation in Human Vascular Cells. [Tang Y, et al. J Am Heart Assoc 2012;1(3):e000901] PubMed: 23130137






















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