Histone Deacetylases (HDACs) are among the most attractive and interesting targets in anticancer drug discovery. The clinical relevance of HDAC inhibitors (HDACIs) is testified by four FDA-approved drugs for cancer treatment. However, one of the main drawbacks of these drugs resides in the lack of selectivity against the different HDAC isoforms, resulting in severe side effects. Thus, the identification of selective HDACIs represents an exciting challenge for medicinal chemists. HDACIs are composed of a cap group, a linker region, and a metal-binding group interacting with the catalytic zinc ion. While the cap group has been extensively investigated, less information is available about the effect of the linker on isoform selectivity. To this aim, in this work, we explored novel linker chemotypes to direct isoform selectivity. A small library of 25 hydroxamic acids with hitherto unexplored linker chemotypes was prepared. In vitro tests demonstrated that, depending on the linker type, some candidates selectively inhibit HDAC1 over HDAC6 isoform or vice versa. Docking calculations were performed to rationalize the effect of the novel linker chemotypes on biologic activity. Moreover, four compounds were able to increase the levels of acetylation of histone H3 or tubulin. These compounds were also assayed in breast cancer MCF7 cells to test their antiproliferative effect. Three compounds showed a significant reduction of cancer proliferation, representing valuable starting points for further optimization.

Investigation of the effect of different linker chemotypes on the inhibition of histone deacetylases (HDACs) / Linciano, P.; Benedetti, R.; Pinzi, L.; Russo, F.; Chianese, U.; Sorbi, C.; Altucci, L.; Rastelli, G.; Brasili, L.; Franchini, S.. - In: BIOORGANIC CHEMISTRY. - ISSN 0045-2068. - 106:(2021), pp. 104462-104462. [10.1016/j.bioorg.2020.104462]

Investigation of the effect of different linker chemotypes on the inhibition of histone deacetylases (HDACs)

Pinzi L.;Russo F.;Sorbi C.;Rastelli G.;Brasili L.;Franchini S.
2021

Abstract

Histone Deacetylases (HDACs) are among the most attractive and interesting targets in anticancer drug discovery. The clinical relevance of HDAC inhibitors (HDACIs) is testified by four FDA-approved drugs for cancer treatment. However, one of the main drawbacks of these drugs resides in the lack of selectivity against the different HDAC isoforms, resulting in severe side effects. Thus, the identification of selective HDACIs represents an exciting challenge for medicinal chemists. HDACIs are composed of a cap group, a linker region, and a metal-binding group interacting with the catalytic zinc ion. While the cap group has been extensively investigated, less information is available about the effect of the linker on isoform selectivity. To this aim, in this work, we explored novel linker chemotypes to direct isoform selectivity. A small library of 25 hydroxamic acids with hitherto unexplored linker chemotypes was prepared. In vitro tests demonstrated that, depending on the linker type, some candidates selectively inhibit HDAC1 over HDAC6 isoform or vice versa. Docking calculations were performed to rationalize the effect of the novel linker chemotypes on biologic activity. Moreover, four compounds were able to increase the levels of acetylation of histone H3 or tubulin. These compounds were also assayed in breast cancer MCF7 cells to test their antiproliferative effect. Three compounds showed a significant reduction of cancer proliferation, representing valuable starting points for further optimization.
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Investigation of the effect of different linker chemotypes on the inhibition of histone deacetylases (HDACs) / Linciano, P.; Benedetti, R.; Pinzi, L.; Russo, F.; Chianese, U.; Sorbi, C.; Altucci, L.; Rastelli, G.; Brasili, L.; Franchini, S.. - In: BIOORGANIC CHEMISTRY. - ISSN 0045-2068. - 106:(2021), pp. 104462-104462. [10.1016/j.bioorg.2020.104462]
Linciano, P.; Benedetti, R.; Pinzi, L.; Russo, F.; Chianese, U.; Sorbi, C.; Altucci, L.; Rastelli, G.; Brasili, L.; Franchini, S.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1226965
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