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
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