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).
产品描述 MS-275抑制HDACs，作用于HDAC1和HDAC3时，IC50分别为0.51 μM和1.7 μM。
靶点 HDAC1 HDAC3
IC50 0.51 μM 1.7 μM [2]
体外研究 MS-275通过作用于2′-氨基而抑制HDACs。MS-275作用于 K562细胞，诱导 p21WAF1/CIP1和凝溶胶蛋白的累积。MS-275作用于A2780细胞，可以降低S期细胞，提高G1期细胞。 MS-275通过抑制HAD而抑制人类肿瘤细胞系，包括 A2780, Calu-3, HL-60, K562, St-4, HT-29, KB-3-1, Capan-1, 4-1St和 HCT-15细胞增殖， IC50 为41.5 nM到4.71 μM。[1]MS-275抑制HDACs，作用于HDAC1和 HDAC3时IC50 分别为0.51 μM和1.7 μM。而对其他的HDACs没有抑制效果，如HDAC4, 6, 8和10。[2]MS-275有效抑制人类白血病和淋巴癌细胞，包括U937, HL-60, K562, 和Jurkat。MS-275可以诱导U937细胞p21CIP1/WAF1 调节的生长和变异Marker (CD11b)的表达。MS-275降低cyclin D1和抗凋亡蛋白Mcl-1与XIAP的表达。[3]
体内研究 MS-275按49 mg/kg剂量作用于除了HCT-15的人类移植瘤都显示出强抗癌活性。[1]MS-275促进恶性实体瘤和恶性血液病的治疗可能性，及生理和畸变基因表达的调节。MS-275和IL-2联用，作用于肾细胞癌显示出强抗癌活性，因为降低调节性T细胞和增强脾细胞的表达。临床实验 MS-275和5-氮杂胞苷联用用于治疗周期性非小细胞肺癌目前处于I/II期临床实验阶段。
特征
推荐的实验操作
激酶实验:
标准HDAC实验 用HDAC buffer按1:6稀释鼠肝内的酶。重组人类HDACs按1:4稀释在HDAC buffer中。用于标准HDAC实验，60 μl HDAC buffer和10 μl 稀释的酶溶液在30oC混合。在HDAC buffer中加入30 μl基底液开始HDAC反应，随后在30oC下温育30分钟。加入100 μl胰蛋白酶溶液终止反应，胰蛋白酶溶液由溶于50 mM Tris-HCl（pH 为8.0）的10 mg/ml 胰蛋白酶, 100 mM NaCl,及 2 μM TSA组成。30oC下温育20分钟， 通过测定460纳米(λex = 390 nm)处的荧光监测AMC的释放。使用释放的AMC校准荧光强度 。用于标准时间过程实验，在初始100 μl HDAC 反应中加入20 pmol 基底物。2-50 pmol 基底物的酶法分析产物获得荧光AMC，通过测量这种荧光AMC来测定 Km值和 Vmax值。使用Hanes 图分析实验数据。记录的AMC信号是针对没有酶而有buffer和基底物的空白区。
细胞试验: [2]
细胞系 A2780, Calu-3, HL-60, K562, St-4, HT-29, KB-3-1, Capan-1, 4-1St和HCT-15细胞
浓度 10 μM 左右
处理时间 3天
方法 5×103个肿瘤细胞接种到96孔板上，加入梯度浓度MS-275培养三天。细胞用0.1 mg/mL中性红在CO2反应器中染色1小时，测定中性红与50 μL乙醇和150 μL 0.1 M Na2HPO4溶解后的OD540,测定IC50值。
动物实验:
动物模型 侧腹皮下注射A2780, HT-29, HTC-15, KB-3-1, 4-1St, St-4, Capan-1和Calu-3细胞的裸鼠
配制 溶于0.05 N HCl, 0.1% Tween-80
剂量 12.3, 24.5和49 mg/kg
给药处理 每天口服处理一次，每周进行5天，持续4周。
溶解性 (25°C)
• DMSO 75 mg/mL
• 水 <1 mg/mL
• 乙醇 <1 mg/mL
稳定性 2年 -20°C粉状
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
