ACY-738 is an orally active and selective inhibitor of histone deacetylase 6 (HDAC6; IC50=1.7nM). ACY-738 also inhibits the activity of HDAC1 (IC50=94nM), HDAC2 (IC50=128nM), and HDAC3 (IC50=218nM)[1-2]. ACY-738 can be used in research related to neurodegenerative diseases, tumors, inflammation, and autoimmune diseases[3-4].
In vitro, treatment of human multiple myeloma cell lines (such as U266, NCI-H929, etc.) and primary multiple myeloma cells with ACY-738 (5μM or 10μM) for 48 hours significantly induced tumor cell death[5]. Treatment of patient-derived L0, S3, S7 human glioma cells and murine KR158 glioma cells with ACY-738 (0.5–5μM) for 24 hours to 5 days. ACY-738 significantly inhibited tumor cell proliferation[6].
In vivo, intraperitoneal administration of ACY-738 (20mg/kg) to experimental autoimmune encephalomyelitis (EAE) mice on days 9 and 10 post-immunization significantly delayed disease onset, reduced disease severity, and improved short-term memory[7]. Intraperitoneal administration of ACY-738 (5mg/kg or 20mg/kg) to NZB/W F1 mice five days a week for 16 weeks. ACY-738 significantly alleviated the severity of proteinuria and improved mouse survival. ACY-738 increased the proportion of splenic regulatory T cells and reduced the deposition of IgG and C3 immune complexes in the kidneys, as well as SLE-related renal pathological damage[8].
References:
[1] Jochems J, Boulden J, Lee BG, et al. Antidepressant-like properties of novel HDAC6-selective inhibitors with improved brain bioavailability. Neuropsychopharmacology. 2014 Jan;39(2):389-400.
[2] Ren J, Liao X, Vieson MD, et al. Selective HDAC6 inhibition decreases early stage of lupus nephritis by down-regulating both innate and adaptive immune responses. Clin Exp Immunol. 2018 Jan;191(1):19-31.
[3] Majid T, Griffin D, Criss Z 2nd, et al. Pharmocologic treatment with histone deacetylase 6 inhibitor (ACY-738) recovers Alzheimer's disease phenotype in amyloid precursor protein/presenilin 1 (APP/PS1) mice. Alzheimers Dement (N Y). 2015 Oct 11;1(3):170-181.
[4] Xu D, Luo XM, Reilly CM. HDAC6 Deletion Decreases Pristane-induced Inflammation. Immunohorizons. 2024 Sep 1;8(9):668-678.
[5] Mithraprabhu S, Khong T, Jones SS, et al. Histone deacetylase (HDAC) inhibitors as single agents induce multiple myeloma cell death principally through the inhibition of class I HDAC. Br J Haematol. 2013 Aug;162(4):559-62.
[6] Shi P, Hoang-Minh LB, Tian J, et al. HDAC6 Signaling at Primary Cilia Promotes Proliferation and Restricts Differentiation of Glioma Cells. Cancers (Basel). 2021 Apr 1;13(7):1644.
[7] Regna NL, Vieson MD, Luo XM, et al. Specific HDAC6 inhibition by ACY-738 reduces SLE pathogenesis in NZB/W mice. Clin Immunol. 2016 Jan;162:58-73.
[8] LoPresti P. The Selective HDAC6 Inhibitor ACY-738 Impacts Memory and Disease Regulation in an Animal Model of Multiple Sclerosis. Front Neurol. 2019 Jun 28;10:519.
ACY-738是一种具有口服活性的选择性组蛋白去乙酰化酶6（HDAC6；IC50=1.7nM）抑制剂。ACY-738 还可以抑制HDAC1（IC50=94nM），HDAC2（IC50=128nM）和HDAC3（IC50=218nM）的活性[1-2]。ACY-738可用于神经退行性疾病、肿瘤、炎症与自身免疫疾病的相关研究[3-4]。
在体外，ACY-738（5μM或10μM）处理人多发性骨髓瘤细胞系（如U266、NCI-H929等）及原代多发性骨髓瘤细胞48小时，显著诱导肿瘤细胞死亡[5]。ACY-738（0.5–5μM）处理患者来源的L0、S3、S7人胶质瘤细胞及小鼠KR158胶质瘤细胞24小时至5天。ACY-738显著抑制肿瘤细胞增殖[6]。
在体内，ACY-738（20mg/kg）在免疫后第9天和第10天对实验性自身免疫性脑脊髓炎（EAE）小鼠进行腹腔注射处理，显著延缓了疾病发作并减轻了疾病严重程度，同时改善了短期记忆[7]。ACY-738（5mg/kg或20mg/kg）每周5天腹腔注射于NZB/W F1小鼠，连续16周。ACY-738显著减轻了蛋白尿严重程度，提高了小鼠存活率。ACY-738增加了脾脏调节性T细胞的比例，并降低了肾脏中IgG和C3的免疫复合物沉积及SLE相关的肾脏病理损伤[8]。