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. 2022 Feb 12;50(5):2566–2586. doi: 10.1093/nar/gkac081

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© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

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Figure 1. — Characterization of new PAOA derivatives for mechanisms of action and anti-proliferative activities in LMS cells. (A) Characteristic and chemical structures of different PAOA derivatives used in this study in comparison with BML-210 and NKL54. The IC50 in SK-UT-1 cells is show as well as the Plants/PLP docking energies for the compound assayed in this study. The Tanimoto coefficient is reported for all the compounds versus the reference BML-210. *Energy calculated on the re-docked ligand extracted from the 3MU6 complex available from PDB. **Tanimoto similarity index calculated with radius 2 circular Morgan fingerprints (73) in a python script (74) using the RDKit library (75). (B) BML-210, NKL54, (MC2983, MC2984, MC2985 and MC2991 docked conformations in the MEF2A (pdb entry code 3MU6) hydrophobic groove. Plants/PLP combination as implemented in 3d-qsar.com was used to dock the compounds. Lowest energy docked conformations were imported in UCSF Chimera along with the cleaned minimized MEF2A protein and co-crystallized BML-210, for binding mode inspection and comparison. (C) Analysis of cell death in SK-UT-1 cells as percentage of PI positive cells treated with the indicated compounds. Cell death was scored after 48 h from treatments. Data are from three independent experiments, + S.D. (D) Analysis of cell death in DMR cells as percentage of PI positive cells treated with the indicated compounds. Cell death was scored after 48 h from treatments. Data are from three independent experiments, + S.D. (E) Analysis of cell death in SK-LMS-1 cells as percentage of PI positive cells treated with the indicated compounds. Cell death was scored after 48 h from treatments. Data are from 3 independent experiments, + S.D. (F) Lys-deacetylase activity as measured from SK-UT-1 cells treated with increasing concentrations of the indicated compounds [1, 5, 10 μM]. Data are from three independent experiments, + S.D. (G) Immunoblotting analysis of H3K9 acetylation levels in SK-UT-1 cells treated with SAHA [2.5 μM], NKL54, MC2984 and MC2985 [5μM] for the indicated minutes. (H) Dose response curves of NKL54 against a panel of indicated HDAC isozymes using standard enzyme activity assays. (I) Dose response curves of SAHA against a panel of indicated HDAC isozymes using standard enzyme activity assays.