Lipophilic modification of Salirasib modulate the antiproliferative and antimigratory activity

Ballari, María Sol; Porta, Exequiel O.J.; Arel Zalazar, Evelyn; Borini Etichetti, Carla M.; Padrón, José M.; Girardini, Javier; Labadie, Guillermo R.

Abstract

Salirasib, or farnesylthiosalicylic acid (FTS), is a salicylic acid derivative with demonstrated antineoplastic activity. While designed as a competitor of the substrate S-farnesyl cysteine on Ras, it is a potent competitive inhibitor of isoprenylcysteine carboxymethyl transferase. In this study, the antiproliferative activity on six different solid tumor cell lines was evaluated with a series of lipophilic thioether modified salirasib analogues, including those with or without a 1,2,3-triazole linker. A combination of bioassay, cheminformatics, docking, and in silico ADME-Tox was also performed. SAR analysis that analogues with three or more isoprene units or a long aliphatic chain exhibited the most potent activity. Furthermore, three compounds display superior antiproliferative activity than salirasib and similar potency compared to control anticancer drugs across all tested solid tumor cell lines. In addition, the behavior of the collection on migration and invasion, a key process in tumor metastasis, was also studied. Three analogues with specific antimigratory activity were identified with differential structural features being interesting starting points on the development of new antimetastatic agents.

Citation

Ballari, M. S., Porta, E. O., Arel Zalazar, E., Borini Etichetti, C. M., Padrón, J. M., Girardini, J., & Labadie, G. R. (2023). Lipophilic modification of Salirasib modulate the antiproliferative and antimigratory activity. Bioorganic and Medicinal Chemistry, 92, Article 117417. https://doi.org/10.1016/j.bmc.2023.117417

• Journal Article Type: Article
• Acceptance Date: Jul 16, 2023
• Online Publication Date: Jul 17, 2023
• Publication Date: Sep 7, 2023
• Deposit Date: Jun 20, 2023
• Journal: Bioorganic & Medicinal Chemistry
• Print ISSN: 0968-0896
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 92
• Article Number: 117417
• DOI: https://doi.org/10.1016/j.bmc.2023.117417
• Public URL: https://durham-repository.worktribe.com/output/1172104
• Related Public URLs: https://chemrxiv.org/engage/chemrxiv/article-details/644801f2e4bbbe4bbf3d6796