HBX 41108

HBX 41108 is a potent inhibitor of USP7 with IC₅₀ value of 424nM ^[1]. HBX 41108 is shown to affect USP7-mediated p53 deubiquitinating in vitro and in cells ^[1].

In vitro, HBX 41108 inhibited HCT116 proliferation in a dose-dependent manner with an IC₅₀ value of 1μM. HBX 41108 induced the apoptosis of HCT116 in a dose-dependent manner within the concentration range of 0-16μM. Treatment with 1-10μM HBX 41108 for 24 hours resulted in a dose-dependent increase in the levels of p53 and its target gene products in HCT116. 10-50μM HBX 41108 for 24 hours increased the multi-ubiquitination level of p53 in 293T cells overexpressing USP7 ^[1]. 5μM HBX 41108 reduced cell cycle arrest and cell senescence in HUVECs treated with AGEs ^[2]. 20μM HBX 41108 for 2 hours abolished the increase in PPARγ stability induced by HAUSP in COS7 cells ^[3]. 10μM and 25μM HBX 41108 increased the hTPH2 promoter activity in a dose-dependent manner in RN46A cells ^[4].

In vivo, HBX 41108 (100mg/kg) decreased blood glucose levels and improved wound healing rate in diabetic rats, via intraperitoneal injection over 14 days ^[2].

References:
[1]. Colland F, Formstecher E, Jacq X, et al. Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells. Mol Cancer Ther. 2009;8(8):2286-2295.
[2]. Li X, Wang T, Tao Y, Wang X, Li L, Liu J. Inhibition of USP7 suppresses advanced glycation end-induced cell cycle arrest and senescence of human umbilical vein endothelial cells through ubiquitination of p53. Acta Biochim Biophys Sin (Shanghai). 2022;54(3):311-320.
[3]. Lee KW, Cho JG, Kim CM, et al. Herpesvirus-associated ubiquitin-specific protease (HAUSP) modulates peroxisome proliferator-activated receptor γ (PPARγ) stability through its deubiquitinating activity. J Biol Chem. 2013;288(46):32886-32896.
[4]. Nawa Y, Kaneko H, Oda M, et al. Functional characterization of the neuron-restrictive silencer element in the human tryptophan hydroxylase 2 gene expression. J Neurochem. 2017;142(6):827-840.

HBX 41108是USP7的强效抑制剂，其IC₅₀值为424nM^[1]。HBX 41108在体外和细胞中均能影响USP7介导的p53蛋白去泛素化^[1]。

在体外，HBX 41108以剂量依赖的方式抑制HCT116细胞的增殖，其IC₅₀值为1μM。HBX 41108在0-16μM的浓度范围内以剂量依赖的方式诱导HCT116细胞凋亡。用1-10μM的HBX 41108处理24小时，会导致HCT116细胞中p53及其靶基因产物的水平呈剂量依赖性增加。10-50μM的HBX 41108处理24小时会使过表达USP7的293T细胞中p53蛋白多泛素化水平升高^[1]。5μM的HBX 41108能减缓AGEs处理的HUVECs中细胞周期停滞和细胞衰老^[2]。20μM的HBX 41108处理2小时可抑制COS7细胞中HAUSP诱导的PPARγ稳定性的增加^[3]。10μM和25μM的HBX 41108以剂量依赖的方式增加了RN46A细胞中hTPH2启动子的活性^[4]。

在体内，以100mg/kg的剂量将HBX 41108腹腔注射到有伤口的糖尿病大鼠中，14天后大鼠血糖水平降低，伤口愈合率提高^[2]。