RepSox
{{Short description|Chemical compound}}
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{{Drugbox
| drug_name =
| IUPAC_name = 2-[5-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl]-1,5-naphthyridine
| image = RepSox2.svg
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| pregnancy_AU =
| pregnancy_US = N
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| legal_status = Unscheduled
| routes_of_administration = Oral
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| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 446859-33-2
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = JT8ZW3H2ST
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| ATC_prefix = none
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| PubChem = 449054
| DrugBank =
| ChemSpiderID = 395681
| ChEMBL = 185238
| ChEBI = 190969
| C=17 | H=13 | N=5
| smiles = CC1=NC(=CC=C1)C2=C(C=NN2)C3=NC4=C(C=C3)N=CC=C4
| StdInChI = InChI=1S/C17H13N5/c1-11-4-2-5-16(20-11)17-12(10-19-22-17)13-7-8-14-15(21-13)6-3-9-18-14/h2-10H,1H3,(H,19,22)
| StdInChIKey = LBPKYPYHDKKRFS-UHFFFAOYSA-N
}}
RepSox is a small molecule inhibitor of TGFβR1,{{cite journal | vauthors = Mei L, Sang W, Chen Z, Zheng L, Jin K, Lou C, Huang W, He D | title = Small molecule inhibitor RepSox prevented ovariectomy-induced osteoporosis by suppressing osteoclast differentiation and bone resorption | journal = Journal of Cellular Physiology | volume = 233 | issue = 12 | pages = 9724–9738 | date = December 2018 | pmid = 30059597 | doi = 10.1002/jcp.26914 | s2cid = 51867699 }}{{cite journal | vauthors = Mishra T, Bhardwaj V, Ahuja N, Gadgil P, Ramdas P, Shukla S, Chande A | title = Improved loss-of-function CRISPR-Cas9 genome editing in human cells concomitant with inhibition of TGF-β signaling | journal = Molecular Therapy. Nucleic Acids | volume = 28 | pages = 202–218 | date = June 2022 | pmid = 35402072 | pmc = 8961078 | doi = 10.1016/j.omtn.2022.03.003 }} also known as ALK5. As a mimetic of the effects of the SOX2 protein, it has gained attention in the fields of stem cell research and regenerative medicine.
It was identified after the discovery of the Yamanaka factors.{{cite journal | vauthors = Baker M |title=RepSox hits a home run |url=https://www.nature.com/articles/stemcells.2009.130 |journal=Nature Reports Stem Cells |pages=1 |language=en |doi=10.1038/stemcells.2009.130 |date=15 October 2009}} 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.{{cite journal | vauthors = Gellibert F, Woolven J, Fouchet MH, Mathews N, Goodland H, Lovegrove V, Laroze A, Nguyen VL, Sautet S, Wang R, Janson C, Smith W, Krysa G, Boullay V, De Gouville AC, Huet S, Hartley D | title = Identification of 1,5-naphthyridine derivatives as a novel series of potent and selective TGF-beta type I receptor inhibitors | journal = Journal of Medicinal Chemistry | volume = 47 | issue = 18 | pages = 4494–4506 | date = August 2004 | pmid = 15317461 | doi = 10.1021/jm0400247 }} RepSox is a member of the 1,5-naphthyridine class.
Research
In an in-vivo trial of rats with ovariectomy-induced osteoporosis, RepSox was shown to prevent bone loss. RepSox is included as a part of some chemical cocktails intended for cellular reprogramming and anti-aging,{{cite journal | vauthors = Knyazer A, Bunu G, Toren D, Mracica TB, Segev Y, Wolfson M, Muradian KK, Tacutu R, Fraifeld VE | title = Small molecules for cell reprogramming: a systems biology analysis | journal = Aging | volume = 13 | issue = 24 | pages = 25739–25762 | date = December 2021 | pmid = 34919532 | pmc = 8751603 | doi = 10.18632/aging.203791 }} where it works by inducing the expression of the gene Nanog.{{cite journal | vauthors = Ichida JK, Blanchard J, Lam K, Son EY, Chung JE, Egli D, Loh KM, Carter AC, Di Giorgio FP, Koszka K, Huangfu D, Akutsu H, Liu DR, Rubin LL, Eggan K | title = A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog | journal = Cell Stem Cell | volume = 5 | issue = 5 | pages = 491–503 | date = November 2009 | pmid = 19818703 | pmc = 3335195 | doi = 10.1016/j.stem.2009.09.012 }}
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.{{cite journal | vauthors = He D, Gao J, Zheng L, Liu S, Ye L, Lai H, Pan B, Pan W, Lou C, Chen Z, Fan S | title = TGF‑β inhibitor RepSox suppresses osteosarcoma via the JNK/Smad3 signaling pathway | journal = International Journal of Oncology | volume = 59 | issue = 5 | date = November 2021 | pmid = 34533199 | pmc = 8460063 | doi = 10.3892/ijo.2021.5264 }}
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.{{cite journal | vauthors = Shi CJ, Lian JJ, Zhang BW, Cha JX, Hua QH, Pi XP, Hou YJ, Xie X, Zhang R | title = TGFβR-1/ALK5 inhibitor RepSox induces enteric glia-to-neuron transition and influences gastrointestinal mobility in adult mice | journal = Acta Pharmacologica Sinica | volume = 44 | issue = 1 | pages = 92–104 | date = January 2023 | pmid = 35794374 | pmc = 9813375 | doi = 10.1038/s41401-022-00932-4 }}
History
RepSox 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.