Entinostat (MS-275,SNDX-275) is a potent, orally available inhibitor of histone deacetylases (HDACs), with IC₅₀ values of 0.368µM for HDAC1 and 0.501µM for HDAC3, but exhibits relatively weak inhibition of HDAC8[1]. HDACs are associate with a number of well characterized cellular oncogenes and tumor suppressor genes. Entinostat exhibits anti-proliferative activity in vitro in many different human cancer cell lines including breast, colon, lung, myeloma, ovary, pancreas, prostate and leukemia in vivo antitumor activity and also demonstrates antitumor activity in vivo in animal models[1]. Entinostat has been used in preclinical studies for cancer treatment[2].
In vitro, Entinostat (0.1-100µM; 24-72h) inhibited the proliferation of human Y79 and Weri-Rb1 cells in a dose- and time-dependent manner, with GI₅₀ values of 1.34 and 0.98µM for Y79 and Weri-Rb1 cells, respectively, at 72h[3].
In vivo, Entinostat (20mg/kg; i.p.) administered every other day for 21 days reduced ocular tumor burden by 76% in LHh-Tag mice[3]. Entinostat (20mg/kg; i.p.) administered every other day for 13 days reduced ocular tumor burden by 63% in the rat ocular xenograft model[3]. Entinostat (3.5mg/kg; i.p.) administered for 5 days greatly reduced the severity and duration of experimental autoimmune neuritis (EAN), attenuated the local accumulation of macrophages, T cells, and B cells, as well as demyelination of the sciatic nerves, in rats with EAN induced by the neuritogenic synthetic P2 peptide[4].
References:
[1] Hess-Stumpp, Holger et al. “MS-275, a potent orally available inhibitor of histone deacetylases--the development of an anticancer agent.” The international journal of biochemistry & cell biology vol. 39,7-8 (2007): 1388-405.
[2] Pili, R et al. “Phase I study of the histone deacetylase inhibitor entinostat in combination with 13-cis retinoic acid in patients with solid tumours.” British journal of cancer vol. 106,1 (2012): 77-84.
[3] Dalgard, Clifton Lee et al. “Evaluation of the in vitro and in vivo antitumor activity of histone deacetylase inhibitors for the therapy of retinoblastoma.” Clinical cancer research : an official journal of the American Association for Cancer Research vol. 14,10 (2008): 3113-23.
[4] Zhang, Z Y et al. “MS-275, an histone deacetylase inhibitor, reduces the inflammatory reaction in rat experimental autoimmune neuritis.” Neuroscience vol. 169,1 (2010): 370-7.
Entinostat (MS-275,SNDX-275)是一种强效的、可口服的组蛋白去乙酰化酶（HDACs）抑制剂，对HDAC1和HDAC3的IC₅₀分别为0.368µM和0.501µM，但对HDAC8的抑制作用相对较弱[1]。HDACs 与许多已明确特征的细胞癌基因和肿瘤抑制基因有关。Entinostat在体外对许多不同的人类癌细胞系，包括乳腺癌、结肠癌、肺癌、骨髓瘤、卵巢癌、胰腺癌、前列腺癌和白血病，显示出抗增殖活性，在动物模型中也显示出抗肿瘤活性[1]。Entinostat已用于癌症治疗的临床前研究中[2]。
体外实验中，Entinostat（0.1-100µM；24-72h）以剂量依赖和时间依赖的方式抑制人Y79和Weri-Rb1细胞的增殖，在72 h时，其对Y79和Weri-Rb1细胞的IC₅₀值分别为1.34和0.98µM[3]。
体内实验中，Entinostat（20mg/kg；i.p.）每隔一天给药，连续21天，使LHh-Tag转基因小鼠眼部肿瘤负荷降低76%[3]。Entinostat（20mg/kg；i.p.）每隔一天给药，连续13天，使大鼠眼异种移植模型的眼部肿瘤负荷降低63%[3]。在神经源性合成P2肽诱导的实验性自身免疫性神经炎（EAN）大鼠中，给予Entinostat（3.5mg/kg；i.p.）5天，可显著降低神经炎严重程度和持续时间，减轻巨噬细胞、T细胞和B细胞的局部积聚，以及坐骨神经脱髓鞘[4]。