NU 9056 (1,2-bis(isothiazol-5-yl) disulfide) is a potent and selective Tip60 (KAT5) histone acetyltransferase (HAT) inhibitor with an IC50 value of 2μM and anti-tumor activity[1, 2]. Tip60 regulates key biological processes such as gene transcription, DNA damage repair, and cell apoptosis by acetylation of histones (such as H4, H2A) and non-histone substrates[3]. NU 9056 is more than 16 times more selective for Tip60 than PCAF, p300, and GCN5[4].
In vitro, NU 9056 (2.5-40μM) treated human anaplastic thyroid carcinoma (ATC) cells (CAL-62 cells) for 48h effectively inhibited ATC cell proliferation in a concentration-dependent manner, reduced the expression levels of intracellular acetyl histone H2A and acetyl histone H4, and inhibited cell migration, invasion, and tube formation[5].
In vivo, NU 9056 (5mg/kg) treated with intraperitoneal injection in mice with lipopolysaccharide (LPS)-induced sepsis-associated encephalopathy (SAE) improved the survival rate of mice and alleviated cognitive impairment, anxiety, and depressive behaviors[6].
References:
[1] Coffey K, Blackburn T J, Cook S, et al. Characterisation of a Tip60 specific inhibitor, NU9056, in prostate cancer[J]. 2012.
[2] Xu L, Qin Y, Liu M, et al. The acetyltransferase KAT5 inhibitor NU 9056 promotes apoptosis and inhibits JAK2/STAT3 pathway in Extranodal NK/T cell lymphoma[J]. Anti-Cancer Agents in Medicinal Chemistry-Anti-Cancer Agents), 2022, 22(8): 1530-1540.
[3] Lashgari A, Tchara P E K, Lambert J P, et al. New insights into the DNA repair pathway choice with NuA4/TIP60[J]. DNA repair, 2022, 113: 103315.
[4] Dansu D K. Changes in the Epigenetic Landscape of Oligodendrocyte Progenitor Cells With Time[D]. City University of New York, 2023.
[5] Xu W, Xie L, Yang Y, et al. KAT5 Inhibitor NU9056 Suppresses Anaplastic Thyroid Carcinoma Progression through c‐Myc/miR‐202 Pathway[J]. International journal of endocrinology, 2022, 2022(1): 2014568.
[6] Chen L, Qing W, Yi Z, et al. NU9056, a KAT 5 inhibitor, treatment alleviates brain dysfunction by inhibiting NLRP3 inflammasome activation, affecting gut microbiota, and derived metabolites in LPS-treated mice[J]. Frontiers in Nutrition, 2021, 8: 701760.
NU 9056（1，2-双（异噻唑-5-基）二硫烷）是一种有效且选择性的Tip60（KAT5） 组蛋白乙酰转移酶（HAT）抑制剂，IC50值为2μM，具有抗肿瘤活性[1, 2]。Tip60通过乙酰化组蛋白（如H4、H2A）和非组蛋白底物，调控基因转录、DNA损伤修复、细胞凋亡等关键生物学过程[3]。NU 9056对Tip60的选择性比PCAF、p300和GCN5高16倍以上[4]。
在体外，NU 9056（2.5-40μM）处理人类间变性甲状腺癌（ATC）细胞（CAL-62 细胞）48h，以浓度依赖性方式有效抑制ATC细胞增殖，降低了细胞内乙酰组蛋白H2A和乙酰组蛋白H4的表达水平，抑制了细胞的迁移、侵袭和管腔形成[5]。
在体内，NU 9056（5mg/kg）通过腹腔注射治疗脂多糖（LPS）诱导的脓毒症相关脑病（SAE）小鼠，提高了小鼠的存活率，并减轻了认知障碍、焦虑和抑郁行为[6]。