RepSox is a potent and selective inhibitor of transforming growth factor-β receptor I/activin-like kinase 5 (TGF-β-RI/ALK5) with an IC50 of 23nM[1]. RepSox inhibits ALK5 autophosphorylation with an IC50 of 4nM[2]. RepSox can be used to study obesity and related metabolic diseases (such as type 2 diabetes)[3].
In vitro, treatment of mouse embryonic fibroblasts with RepSox (10μM) for 8-10days induced the generation of many adipocytes, enhanced brown preadipocyte differentiation, and promoted the browning of white preadipocytes[4]. Treatment of osteosarcoma cell lines (HOS and 143B cells) with RepSox (0-200μM) for 24-96h inhibited cell proliferation in a time- and concentration-dependent manner, significantly inhibited colony size and number, increased the expression of pro-apoptotic Bax protein, and decreased the expression of anti-apoptotic Bcl-2 protein[5].
In vivo, RepSox (3, 10mg/kg) was administered to adult mice via oral gavage for 2 weeks, which significantly promoted the transformation of enteric glial cells into enteric nervous system neurons, affected gastrointestinal motility, and enhanced gastrointestinal motility in mice[6]. RepSox (2, 5mg/kg) was administered intraperitoneally to osteoporosis (OP) model mice for 4 weeks, which prevented bone loss in vivo, reduced the number of osteoclasts, and lowered serum CTX-1 (a bone resorption marker) [7].
References:
[1] Madipally D J. Role of Epicardial Adipose Tissue Secreted Interleukin-34 in Fibroblast to Myofibroblast Transdifferentiation and Atrial Fibrosis[M]. East Carolina University, 2021.
[2] Mansour M A, Hassan G S, Serya R A T, et al. Advances in the discovery of activin receptor-like kinase 5 (ALK5) inhibitors[J]. Bioorganic Chemistry, 2024: 107332.
[3] Takeda Y, Harada Y, Yoshikawa T, et al. Chemical compound-based direct reprogramming for future clinical applications[J]. Bioscience Reports, 2018, 38(3): BSR20171650.
[4] Tu W, Fu Y, Xie X. RepSox, a small molecule inhibitor of the TGFβ receptor, induces brown adipogenesis and browning of white adipocytes[J]. Acta Pharmacologica Sinica, 2019, 40(12): 1523-1531.
[5] He D, Gao J, Zheng L, et al. TGF β inhibitor RepSox suppresses osteosarcoma via the JNK/Smad3 signaling pathway[J]. International Journal of Oncology, 2021, 59(5): 1-13.
[6] Shi C, Lian J, Zhang B, et al. TGFβR-1/ALK5 inhibitor RepSox induces enteric glia-to-neuron transition and influences gastrointestinal mobility in adult mice[J]. Acta Pharmacologica Sinica, 2023, 44(1): 92-104.
[7] Mei L, Sang W, Chen Z, et al. Small molecule inhibitor RepSox prevented ovariectomy‐induced osteoporosis by suppressing osteoclast differentiation and bone resorption[J]. Journal of Cellular Physiology, 2018, 233(12): 9724-9738.
RepSox是一种有效的选择性转化生长因子-β受体I/激活素样激酶5（TGF-β-RI/ALK5）抑制剂，IC50为23nM[1]。RepSox抑制ALK5自身磷酸化，IC50 值为4nM[2]。RepSox可用于肥胖和相关代谢疾病（如2型糖尿病）的研究[3]。
在体外，RepSox（10μM）处理小鼠胚胎成纤维细胞8-10天，诱导了许多脂肪样细胞生成，增强了棕色前脂肪细胞分化，促进了白色前脂肪细胞褐变[4]。RepSox（0-200μM）处理骨肉瘤细胞系（HOS和143B细胞）24-96h，以时间和浓度依赖性方式抑制了细胞增殖，显著抑制了集落大小和数量，增加了促凋亡Bax蛋白的表达，降低了抗凋亡Bcl-2蛋白的表达[5]。
在体内，RepSox（3, 10mg/kg）通过灌胃处理成年小鼠2周，显著促进了肠神经胶质细胞向肠神经系统神经元的转化，并影响了小鼠的胃肠蠕动，增强了胃肠动力[6]。RepSox（2, 5mg/kg）通过腹膜内注射治疗骨质疏松症（OP）模型小鼠4周，防止了体内骨质流失，减少了破骨细胞的数量，降低了血清CTX-1（骨吸收标志物）[7]。