Fig 2: HDAC6 (selective) inhibitor tubastatin A and analogs. Only compounds with a basic nitrogen near the heterocyclic core (14, 16) exhibit strong HDAC10 binding.

Fig 3: A) Stereoview of the Polder omit maps of the HDAC6-3a complex (monomer A, contoured at 3.5 s, PDB 6VNR). Atoms are color-coded as follows: C=light blue (HDAC6), dark gray (symmetry mate), or wheat (inhibitor), N=blue, O=red, Zn2+=gray sphere, and solvent=small red spheres. Metal coordination and hydrogen bond interactions are indicated by solid and dashed black lines, respectively. B) Stereoview of a superposition of the complexes of 3a with HDAC6 and HDAC10. Atoms are color-coded as follows: C=light blue (HDAC6) or white (HDAC10), dark gray (symmetry mate of HDAC6), wheat (3a bound to HDAC6), orange (3a bound to HDAC10), N=blue, O=red, and Zn2+=gray sphere.

Fig 4: Docking pose of (a)-7c (A) and (ß)-7c (B) in the catalytic domain 2 of HDAC6 (PDB: 5EDU [29]). Ligands are colored green and are depicted as sticks. The catalytic Zn2+-ion is shown as a gray sphere, and water is shown as a red sphere. The protein backbone is shown as light blue cartoon including the wheat-colored protein surface surrounding the ligand. The binding interactions of the hydroxamic acids are depicted as yellow, dashed lines.

Fig 5: Off-targets effects of sc1o. (a) For the safety profile and off-target studies of sc1o (CYP3A4, CYP1A2, CYP2D6 inhibition, CYP induction, hERG, HDAC1, HDAC3, HDAC6, PDE4A1, PDE7A1, and PDE8A1), the concentration–response data was fitted to a 4-parameter logistic fit using Prism v5.04 to yield its IC50 in each assay. As sc1o was weakly active, the inhibition percentage at 100 µM was calculated and reported. (b) Inhibition of hERG by sc1o was calculated using the Predictor hERG fluorescence polarization assay. As a positive control E-4031, a blocker of hERG-type potassium channels, yielding 100% inhibition and as negative control 100 nl of 100% v/v DMSO yielding 0% inhibition were added.