Lipophilic modification of Salirasib modulate the antiproliferative and antimigratory activity.

26 April 2023, Version 2
This content is a preprint and has not undergone peer review at the time of posting.


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. Although different salirasib derivatives have been reported, the isoprenyl tail has not been modified. In this study, we used a series of synthetic salirasib analogues with lipophilic thioether modifications, including those with or without a 1,2,3-triazole linker, and tested their antiproliferative activity against six different solid tumor cell lines. We carried out a combination of bioassay, cheminformatics, and in silico ADME-Tox to identify new potent analogues. SAR analysis revealed structural and physicochemical features that enhance antiproliferative activity. Analogues with three or more isoprene units or a long aliphatic chain exhibited the most potent activity. Furthermore, we identified three compounds with superior antiproliferative activity than salirasib and similar potency compared to control anticancer drugs across all tested solid tumor cell lines. In addition, the behaviour of the collection on migration and invasion, the key processes in tumor metastasis, were also studied. Three analogs with specific antimigratory activity were identified with differential structural features. The combination of the antiproliferative and antimigratory results prompts to propose that the modification on the thiol aliphatic/prenyl substituents can modulate the activity. Our findings provide valuable insight on the lipophilic salirasib analogues with enhanced antiproliferative activity against solid tumor cell lines. Also, we have been able to identify analogues with specific antimigratory activity that could be the starting points on the development of new antimetastatic agents.


SAR studies
Cell Migration

Supplementary materials

Supporting information - biological assays and chemoimformatics
General procedure for in vitro antiproliferative activity. In silico Physicochemical properties prediction. SAR analysis. ADMETox.


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