DUBs-IN-2

DUBs-IN-2 is a highly selective and membrane-permeable inhibitor for USP8 with IC₅₀ value of 0.28μM ^[1]. DUBs-IN-2 can activate the NF-κB signaling pathway by inhibiting the activity of USP8, thereby upregulating MHC-I expression ^[2]. DUBs-IN-2 has been widely used as an anti-cancer agent, effectively inhibiting the progression of colon cancer, lung cancer and prostate cancer^[3].

In vitro, DUBs-IN-2 treatment for 3 days significantly inhibited the proliferation of HGC-27 cells, BGC-823 cells, and MGC-803 cells, with IC₅₀ values of 0.72μM, 0.921μM, and 1.219μM, respectively^[4]. Treatment with 2μM DUBs-IN-2 for 6 hours markedly reduced the protein levels of NICD and HES1 in MDA-MB-231 cells^[5]. Treatment with 10μM DUBs-IN-2 for 24 hours remarkably reduced the mRNA levels of Proopiomelanocortin (Pomc) and the protein level of EGFR in AtT-20 cells^[6].

In vivo, DUBs-IN-2 was administered intraperitoneally at a dose of 1mg/kg (5 times per week) for 6 consecutive weeks, which significantly reduced the tumor volume of H1975 cell-xenograft of mice, and downregulated the expressions of phosphorylated EGFR, ERBB3 and c-MET in the tumor tissues^[7]. Continuous intraperitoneal injection of 0.2mg/kg/day dose of DUBs-IN-2 for two consecutive weeks can protect the pulmonary hypertension (PH) rat model from the occurrence and development of experimental PH^[8].

References:
[1] Tsefou E, Ketteler R. Targeting deubiquitinating enzymes (DUBs) that regulate mitophagy via direct or indirect interaction with Parkin[J]. International Journal of Molecular Sciences, 2022, 23(20): 12105.
[2] Hsu S K, Chou C K, Lin I L, et al. Deubiquitinating enzymes: potential regulators of the tumor microenvironment and implications for immune evasion[J]. Cell Communication and Signaling, 2024, 22(1): 259.
[3] Qin B, Chen X, Wang F, et al. DUBs in Alzheimer’s disease: mechanisms and therapeutic implications[J]. Cell Death Discovery, 2024, 10(1): 475.
[4] Sun J, Shen D, Gao Y, et al. Down-regulation of USP8 suppresses HER-3 positive gastric cancer cells proliferation[J]. OncoTargets and therapy, 2020: 7973-7984.
[5] Shin S, Kim K, Kim H R, et al. Deubiquitylation and stabilization of Notch1 intracellular domain by ubiquitin-specific protease 8 enhance tumorigenesis in breast cancer[J]. Cell Death & Differentiation, 2020, 27(4): 1341-1354.
[6] Kageyama K, Asari Y, Sugimoto Y, et al. Ubiquitin-specific protease 8 inhibitor suppresses adrenocorticotropic hormone production and corticotroph tumor cell proliferation[J]. Endocrine journal, 2020, 67(2): 177-184.
[7] Byun S, Lee S Y, Lee J, et al. USP8 is a novel target for overcoming gefitinib resistance in lung cancer[J]. Clinical cancer research, 2013, 19(14): 3894-3904.
[8] Jutant E M, Chelgham M K, Ottaviani M, et al. Central role of ubiquitin-specific protease 8 in leptin signaling pathway in pulmonary arterial hypertension[J]. The Journal of Heart and Lung Transplantation, 2024, 43(1): 120-133.

DUBs-IN-2是一种高度选择性且具有细胞膜渗透性的 USP8 抑制剂，IC₅₀值为0.28μM^[1]。DUBs-IN-2通过抑制USP8的活性，能够激活NF-κB信号通路，从而上调 MHC-I 的表达^[2]。DUBs-IN-2已被广泛用作抗癌剂，能有效抑制结肠癌、肺癌和前列腺癌的进展^[3]。

在体外，DUBs-IN-2处理3天显著抑制了HGC-27细胞、BGC-823细胞和MGC-803细胞的增殖，IC₅₀值分别为0.72μM、0.921μM和1.219μM^[4]。用2μM的DUBs-IN-2处理6小时显著降低了MDA-MB-231细胞中NICD和HES1的蛋白水平^[5]。用10μM的DUBs-IN-2处理24小时显著降低了AtT-20细胞中Proopiomelanocortin（Pomc）的mRNA水平和EGFR的蛋白水平^[6]。

在体内，DUBs-IN-2以1mg/kg剂量腹腔注射（每周5次）连续6周，显著降低了小鼠H1975细胞异种移植瘤的体积，并下调了肿瘤组织中磷酸化EGFR、ERBB3和c-MET的表达^[7]。连续两周腹腔注射0.2mg/kg/day剂量的DUBs-IN-2可保护肺动脉高压（PH）大鼠模型，防止实验性PH的发生和发展^[8]。