RepSox

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. TGFβ 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.