Hydroxamic acid derivatives as HDAC1, HDAC6 and HDAC8 inhibitors with antiproliferative activity in cancer cell lines
Metadatos
Afficher la notice complèteEditorial
Nature Research (part of Springer Nature)
Date
2020-06Referencia bibliográfica
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]
Patrocinador
Consejo Nacional de Ciencia y Tecnologia (CONACyT) CB-254600 SEP-CONACYT-ANUIES-ECOS Francia: 296636; Instituto Politecnico Nacional Proyectos Insignia IPN-2015Résumé
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.