RepSox is a small molecule inhibitor of TGFβR1,[1][2] also known as ALK5, that was first identified in the wake of the discovery of the Yamanaka factors.[3] It has shown promise in a variety of in-vitro and in-vivo rodent trials modelling various diseases. It inhibits TGFβR1 autophosphorylation by preventing the protein from binding with ATP, inhibits the binding of TGF-β to TGFβR1, and prevents the transcription of genes activated by TGFβR1 with nanomolar potency.[4] RepSox is a member of the 1,5-naphthyridine class.
 | |
| Clinical data | |
|---|---|
| Routes of administration | Oral |
| ATC code |
|
| Legal status | |
| Legal status |
|
| Identifiers | |
| |
| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| UNII | |
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.190.188 |
| Chemical and physical data | |
| Formula | C17H13N5 |
| Molar mass | 287.326 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
Research
editIn an in-vivo trial of rats with ovariectomy-induced osteoporosis, RepSox was shown to prevent bone loss.[1] RepSox is included as a part of some chemical cocktails intended for cellular reprogramming and anti-aging,[5] where it works by inducing the expression of the gene Nanog.[6]
RepSox suppresses the proliferation of osteosarcoma cells via suppression of the JNK/Smad3 signalling pathway, and was able to induce cell cycle arrest, promote apoptosis and prevent migration of the cancer cells. The results were replicated both in-vitro and in-vivo.[7]
RepSox was able to promote the transformation of glial cells to neurons in the enteric nervous system of adult mice, consequently influencing gastrointestinal motility, and underlining a potential therapeutic use of RepSox in enteric neuropathies.[8]
History
editRepSox was discovered by a team at the Harvard Stem Cell Institute looking for way to induce pluripotency without inserting the gene Sox2 into cells. They discovered a molecule which was capable of this but also was able to reprogram cells in the absence of c-Myc, a tumour promoting gene. They named the molecule RepSox since it can replace Sox2 and in homage to the Boston Red Sox.[3]
References
edit- ^ a b Mei, Liangwei; Sang, Wenhua; Chen, Zhenzhong; Zheng, Lin; Jin, Kangtao; Lou, Chao; Huang, Wenjun; He, Dengwei (December 2018). "Small molecule inhibitor RepSox prevented ovariectomy-induced osteoporosis by suppressing osteoclast differentiation and bone resorption". Journal of Cellular Physiology. 233 (12): 9724–9738. doi:10.1002/jcp.26914. ISSN 1097-4652. PMID 30059597. S2CID 51867699.
- ^ Mishra, Tarun; Bhardwaj, Vipin; Ahuja, Neha; Gadgil, Pallavi; Ramdas, Pavitra; Shukla, Sanjeev; Chande, Ajit (8 March 2022). "Improved loss-of-function CRISPR-Cas9 genome editing in human cells concomitant with inhibition of TGF-β signaling". Molecular Therapy. Nucleic Acids. 28: 202–218. doi:10.1016/j.omtn.2022.03.003. ISSN 2162-2531. PMC 8961078. PMID 35402072.
- ^ a b Baker, Monya (15 October 2009). "RepSox hits a home run". Nature Reports Stem Cells: 1. doi:10.1038/stemcells.2009.130.
- ^ Gellibert, Françoise; Woolven, James; Fouchet, Marie-Hélène; Mathews, Neil; Goodland, Helen; Lovegrove, Victoria; Laroze, Alain; Nguyen, Van-Loc; Sautet, Stéphane; Wang, Ruolan; Janson, Cheryl; Smith, Ward; Krysa, Gaël; Boullay, Valérie; De Gouville, Anne-Charlotte; Huet, Stéphane; Hartley, David (26 August 2004). "Identification of 1,5-naphthyridine derivatives as a novel series of potent and selective TGF-beta type I receptor inhibitors". Journal of Medicinal Chemistry. 47 (18): 4494–4506. doi:10.1021/jm0400247. ISSN 0022-2623. PMID 15317461.
- ^ Knyazer, Anna; Bunu, Gabriela; Toren, Dmitri; Mracica, Teodora Bucaciuc; Segev, Yael; Wolfson, Marina; Muradian, Khachik K.; Tacutu, Robi; Fraifeld, Vadim E. (17 December 2021). "Small molecules for cell reprogramming: a systems biology analysis". Aging (Albany NY). 13 (24): 25739–25762. doi:10.18632/aging.203791. ISSN 1945-4589. PMC 8751603. PMID 34919532.
- ^ Ichida, Justin K.; Blanchard, Joel; Lam, Kelvin; Son, Esther Y.; Chung, Julia E.; Egli, Dieter; Loh, Kyle M.; Carter, Ava C.; Di Giorgio, Francesco P.; Koszka, Kathryn; Huangfu, Danwei; Akutsu, Hidenori; Liu, David R.; Rubin, Lee L.; Eggan, Kevin (November 2009). "A Small-Molecule Inhibitor of Tgf-β Signaling Replaces Sox2 in Reprogramming by Inducing Nanog". Cell Stem Cell. 5 (5): 491–503. doi:10.1016/j.stem.2009.09.012. PMC 3335195. PMID 19818703.
- ^ He, D; Gao, J; Zheng, L; Liu, S; Ye, L; Lai, H; Pan, B; Pan, W; Lou, C; Chen, Z; Fan, S (November 2021). "TGF‑β inhibitor RepSox suppresses osteosarcoma via the JNK/Smad3 signaling pathway". International Journal of Oncology. 59 (5). doi:10.3892/ijo.2021.5264. PMC 8460063. PMID 34533199.
- ^ Shi, Chang-jie; Lian, Jun-jiang; Zhang, Bo-wen; Cha, Jia-xue; Hua, Qiu-hong; Pi, Xiao-ping; Hou, Yu-jun; Xie, Xin; Zhang, Ru (January 2023). "TGFβR-1/ALK5 inhibitor RepSox induces enteric glia-to-neuron transition and influences gastrointestinal mobility in adult mice". Acta Pharmacologica Sinica. 44 (1): 92–104. doi:10.1038/s41401-022-00932-4. ISSN 1745-7254. PMC 9813375. PMID 35794374.