Hydroxamic acid derivatives as HDAC1, HDAC6 and HDAC8 inhibitors with antiproliferative activity in cancer cell lines Sixto López, Yudibeth Gómez Vidal, José Antonio Histone deacetylases (HDACs) belong to a family of enzymes that remove acetyl groups from the ɛ-amino of histone and nonhistone proteins. Additionally, HDACs participate in the genesis and development of cancer diseases as promising therapeutic targets to treat cancer. Therefore, in this work, we designed and evaluated a set of hydroxamic acid derivatives that contain a hydrophobic moiety as antiproliferative HDAC inhibitors. For the chemical structure design, in silico tools (molecular docking, molecular dynamic (MD) simulations, ADME/Tox properties were used to target Zn2+ atoms and HDAC hydrophobic cavities. The most promising compounds were assayed in diferent cancer cell lines, including hepatocellular carcinoma (HepG2), pancreatic cancer (MIA PaCa-2), breast cancer (MCF-7 and HCC1954), renal cancer (RCC4-VHL and RCC4-VA) and neuroblastoma (SH-SY5Y). Molecular docking and MD simulations coupled to the MMGBSA approach showed that the target compounds have afnity for HDAC1, HDAC6 and HDAC8. Of all the compounds evaluated, YSL-109 showed the best activity against hepatocellular carcinoma (HepG2 cell line, IC50=3.39µM), breast cancer (MCF-7 cell line, IC50=3.41µM; HCC1954 cell line, IC50=3.41µM) and neuroblastoma (SH-SY5Y cell line, IC50=6.42µM). In vitro inhibition assays of compound YSL-109 against the HDACs showed IC50 values of 259.439µM for HDAC1, 0.537nM for HDAC6 and 2.24µM for HDAC8. 2020-07-30T11:51:00Z 2020-07-30T11:51:00Z 2020-06 info:eu-repo/semantics/article Sixto-López, Y., Gómez-Vidal, J. A., de Pedro, N., Bello, M., Rosales-Hernández, M. C., & Correa-Basurto, J. (2020). Hydroxamic acid derivatives as HDAC1, HDAC6 and HDAC8 inhibitors with antiproliferative activity in cancer cell lines. Scientific reports, 10(1), 1-17. [DOI: 10.1038/s41598-020-67112-4] http://hdl.handle.net/10481/63205 10.1038/s41598-020-67112-4 eng http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Atribución 3.0 España Nature Research (part of Springer Nature)