Discovery of a septin-4 covalent binder with antimetastatic activity in a mouse model of melanoma
[Display omitted] •Modulation of the aspartic acid moiety in the antimetastatic agent AA6 was performed.•Key structural elements for inhibition of B16-F10 cells invasiveness were identified.•One model compound CM365 showed antimetastatic effect in mouse model of melanoma.•Proteomics identified Septi...
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Veröffentlicht in: | Bioorganic chemistry 2024-03, Vol.144, p.107164-107164, Article 107164 |
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Format: | Artikel |
Sprache: | eng |
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•Modulation of the aspartic acid moiety in the antimetastatic agent AA6 was performed.•Key structural elements for inhibition of B16-F10 cells invasiveness were identified.•One model compound CM365 showed antimetastatic effect in mouse model of melanoma.•Proteomics identified Septin-4 as the target involved in the antimetastatic effect.•Molecular simulations evidenced key interactions of CM365 and AA6 with the target.
Cancer spreading through metastatic processes is one of the major causes of tumour-related mortality. Metastasis is a complex phenomenon which involves multiple pathways ranging from cell metabolic alterations to changes in the biophysical phenotype of cells and tissues. In the search for new effective anti-metastatic agents, we modulated the chemical structure of the lead compound AA6, in order to find the structural determinants of activity, and to identify the cellular target responsible of the downstream anti-metastatic effects observed. New compounds synthesized were able to inhibit in vitro B16-F10 melanoma cell invasiveness, and one selected compound, CM365, showed in vivo anti-metastatic effects in a lung metastasis mouse model of melanoma. Septin-4 was identified as the most likely molecular target responsible for these effects. This study showed that CM365 is a promising molecule for metastasis prevention, remarkably effective alone or co-administered with drugs normally used in cancer therapy, such as paclitaxel. |
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ISSN: | 0045-2068 1090-2120 |
DOI: | 10.1016/j.bioorg.2024.107164 |