Thiomyristoyl is a highly potent and specific SIRT2 inhibitor (IC50 = 28 nM) [1]. Thiomyristoyl forms a strong interaction with the catalytic site of SIRT2, competitively blocking the binding of natural substrates to NAD⁺, thereby significantly reducing the deacetylation levels of SIRT2-catalyzed substrates such as α-tubulin, p53, and NF-κB, thus affecting cellular metabolic homeostasis, stress response, and cell cycle regulation [2-3]. Thiomyristoyl is commonly used for its effects in neurodegenerative diseases, oncology, and colitis [4].
In A375 cells, Thiomyristoyl (50μM; 72h) increased sensitivity to cisplatin and exhibited increased accumulation of γ-H2AX and reduced EGFR-AKT-RAF-ERK1/2 pathway signaling compared to control cells [5]. In LNCaP cells, Thiomyristoyl (0.1-100μM; 72h) inhibits the deacetylation activity of SIRT2, blocks its mediated G1/S cell cycle transition, weakens cell proliferation, and promotes tumor cell apoptosis [6].
In dextran sulfate sodium-induced colitis mice model, Thiomyristoyl (5mg/kg; ip; 21d) alleviates colitis inflammation and tissue damage by inhibiting SIRT2 activity, weakening Th17 cell differentiation and pro-inflammatory signals such as IL-17A, p-STAT3, and p-NF-κB, restoring LDHA acetylation, and upregulating IL-10 [7]. In dextran sulfate sodium-induced colitis mice model, Thiomyristoyl (50mg/kg; ip; 10d) significantly improves inflammatory damage and disease activity index by inhibiting the deacetylation activity of SIRT2, alleviating symptoms such as colon shortening, weight loss, and increased mortality in colitis mice [8].
References:
[1]. Jing H, Hu J, He B, et al. A SIRT2-selective inhibitor promotes c-Myc oncoprotein degradation and exhibits broad anticancer activity[J]. Cancer cell, 2016, 29(3): 297-310.
[2]. Li Y, Han L, Fu Y, et al. The role of SIRT2 in homeostatic medicine and aging intervention[J]. Oral Science and Homeostatic Medicine, 2025.
[3]. Shenk T, Kulp III J L, Chiang L W. Drugs Targeting Sirtuin 2 Exhibit Broad-Spectrum Anti-Infective Activity[J]. Pharmaceuticals, 2024, 17(10): 1298.
[4]. Akter R, Afrose A, Rahman M R, et al. A comprehensive analysis into the therapeutic application of natural products as SIRT6 modulators in Alzheimer’s disease, aging, cancer, inflammation, and diabetes[J]. International journal of molecular sciences, 2021, 22(8): 4180.
[5]. Karwaciak I, Sałkowska A, Karaś K, et al. Targeting SIRT2 sensitizes melanoma cells to cisplatin via an EGFR-dependent mechanism[J]. International Journal of Molecular Sciences, 2021, 22(9): 5034.
[6]. Lin R, Yang Y, Wu E, et al. SIRT2 promotes cell proliferation and migration through mediating ERK1/2 activation and lactosylceramide accumulation in prostate cancer[J]. The Prostate, 2023, 83(1): 71-81.
[7]. Xu Y, Cai R, Zhao Z, et al. Thiomyristoyl ameliorates colitis by blocking the differentiation of Th17 cells and inhibiting SIRT2-induced metabolic reprogramming[J]. International Immunopharmacology, 2021, 90: 107212.
[8]. Hou D, Yu T, Lu X, et al. Sirt2 inhibition improves gut epithelial barrier integrity and protects mice from colitis[J]. Proceedings of the National Academy of Sciences, 2024, 121(18): e2319833121.
Thiomyristoyl是一种高效且特异性的SIRT2抑制剂（IC50 = 28 nM） [1]。Thiomyristoyl与SIRT2的催化位点形成强相互作用，竞争性阻断天然底物与NAD⁺的结合，从而显著降低SIRT2催化底物（如α-微管蛋白、p53和NF-κB）的去乙酰化水平，进而影响细胞代谢稳态、应激反应和细胞周期调控 [2-3]。硫代肉豆蔻酰常用于治疗神经退行性疾病、肿瘤和结肠炎 [4]。
在A375细胞中，与对照组细胞相比，Thiomyristoyl（50μM；72h）可提高细胞对cisplatin的敏感性，并表现出γ-H2AX积累增加和EGFR-AKT-RAF-ERK1/2信号通路活性降低 [5]。在LNCaP细胞中，Thiomyristoyl（0.1-100μM；72h）抑制SIRT2的去乙酰化活性，阻断其介导的G1/S细胞周期转换，减弱细胞增殖，并促进肿瘤细胞凋亡 [6]。
在dextran sulfate sodium诱导的小鼠结肠炎模型中，Thiomyristoyl（5mg/kg；ip；21d）通过抑制SIRT2活性、减弱Th17细胞分化和IL-17A、p-STAT3和p-NF-κB等促炎信号、恢复LDHA乙酰化以及上调IL-10，减轻结肠炎炎症和组织损伤 [7]。在dextran sulfate sodium诱导的小鼠结肠炎模型中，Thiomyristoyl（50mg/kg；ip；10d）通过抑制SIRT2的脱乙酰化活性，显著改善炎症损伤和疾病活动指数，缓解结肠炎小鼠的结肠缩短、体重减轻和死亡率增加等症状 [8]。