Oxaprozin and SB-431542 Hybrid Molecule Inhibits Fibrosis and Cancer Cell Migration

Abstract

In this study, we synthesized a novel oxaprozin and SB-431542 hybrid molecule, AF-3, exhibiting antifibrotic and anti-cell-migration activities. Although oxaprozin was expected to exhibit antifibrotic activity, this was not observed in this study. Therefore, we designed AF-3 as an oxaprozin derivative and obtained its synthetic precursor, AF-2. Carboxylic acid AF-2 and carboxamide AF-3 showed similar inhibitory activities against AKT phosphorylation and expression of the mesenchymal cell marker, vimentin. Notably, AF-2 exerted weaker effects on cell migration and fibrosis than AF-3. Although the underlying mechanisms remain elusive, this study provides valuable insights for the development of new drugs against fibrosis and cancer metastasis related to cell migration.

Key words

oxaprozin - SB-431542 - hybrid molecule - anti-fibrotic activity - anti-cell migration activity - vimentin - AKT

Publikationsverlauf

Eingereicht: 13. Oktober 2024

Angenommen nach Revision: 11. Dezember 2024

Accepted Manuscript online:
11. Dezember 2024

Artikel online veröffentlicht:
21. Januar 2025

• References and Notes

• 1 Gordon MK, Hahn RA. Cell Tissue Res. 2010; 339: 247
• 2 Diegelmann RF, Evans MC. Front. Biosci., Landmark Ed. 2004; 9: 283
• 3 Wynn TA. J. Pathol. 2008; 214: 199
• 4 Ruwanpura SM, Thomas BJ, Bardin PG. Am. J. Respir. Cell Mol. Biol. 2020; 62: 413
• 5 Wollin L, Wex E, Pautsch A, Schnapp G, Hostettler KE, Stowasser S, Kolb M. Eur. Respir. J. 2015; 45: 1434
• 6 Li X, Zhu L, Wang B, Yuan M, Zhu R. Front. Pharmacol. 2017; 8: 855
• 7 Mutsaers HA. M, Merrild C, Nørregaard R, Plana-Ripoll O. J. Transl. Med. 2023; 21: 818
• 8 Qin W, Cao L, Massey IY. Mol. Cell. Biochem. 2021; 476: 4045
• 9 Wang J, Hu K, Cai X, Yang B, He Q, Wang J, Weng Q. Acta Pharm. Sin. B 2022; 12: 18
• 10 Montecucco F, Bertolotto M, Ottonello L, Quercioli A, Mach F, Dallegri F. J. Biomed. Biotechnol. 2009; 478785
• 11 Ottonello L, Bertolotto M, Montecucco F, Bianchi G, Dallegri F. Br. J. Pharmacol. 2009; 157: 294
• 12 Bertolotto M, Contini P, Ottonello L, Pende A, Dallegri F, Montecucco F. Br. J. Pharmacol. 2014; 171: 3376
• 13 Giard DJ, Aaronson SA, Todaro GJ, Arnstein P, Kersey JH, Dosik H, Parks WP. J. Natl. Cancer Inst. 1973; 51: 1417
• 14 Kamo M, Ito M, Toma T, Gotoh H, Shimozono R, Nakagawa R, Koga R, Monde K, Tateishi H, Misumi S, Otsuka M, Fujita M. Bioorg. Chem. 2021; 107: 104627
• 15 Toma T, Tateishi H, Kawakami K, Ali TF. S, Kamo M, Monde K, Nakashima Y, Fujita M, Otsuka M. Int. J. Mol. Sci. 2022; 23: 5047
• 16 Fujita M, Akari H, Sakurai A, Yoshida A, Chiba T, Tanaka K, Strebel K, Adachi A. Microbes Infect. 2004; 6: 791
• 17 Inman GJ, Nicolás FJ, Callahan JF, Harling JD, Gaster LM, Reith AD, Laping NJ, Hill CS. Mol. Pharmacol. 2002; 62: 65
• 18 Laping NJ, Grygielko E, Mathur A, Butter S, Bomberger J, Tweed C, Martin W, Fornwald J, Lehr R, Harling J, Gaster L, Callahan JF, Olson BA. Mol. Pharmacol. 2002; 62: 58
• 19 Garneau-Tsodikova S, Thannickal VJ. Curr. Med. Chem. 2008; 15: 2632
• 20 Kasuya Y, Kim JD, Hatano M, Tatsumi K, Matsuda S. Int. J. Mol. Sci. 2021; 22: 6041
• 21 Speckmeier E, Zeitler K. ACS Catal. 2017; 7: 6821
• 22 Fujita M, Tateishi H, Kobayashi-Kai S, Inoue R, Otsuka M. Japan Patent 2023; 2023
• 23 Marconi GD, Fonticoli L, Rajan TS, Pierdomenico SD, Trubiani O, Pizzicannella J, Diomede F. Cells 2021; 10: 1587
• 24 Sisto M, Ribatti D, Lisi S. Biomolecules 2021; 11: 310
• 25 Reka AK, Kuick R, Kurapati H, Standiford TJ, Omenn GS, Keshamouni VG. J. Thorac. Oncol. 2011; 6: 1784