Discovery of 1-benzhydryl piperazine-based HDAC inhibitors with anti-cancer and anti-metastatic properties against human breast cancer: synthesis, molecular modeling, in vitro and in vivo biological evaluation

Abstract

Isoform-selective histone deacetylase (HDAC) inhibition is promoted as a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC inhibitors. Despite this presumed benefit, considerably more non-selective HDAC inhibitors have undergone clinical trials. In this report, we detail the design and discovery of potent HDAC inhibitors with 1-benzhydryl piperazine as a surface recognition group that differ in hydrocarbon linker. Surprisingly, in vitro HDAC screening identified two selective HDAC6 inhibitors (6b, IC50 = 186 nM and 9b, IC50 = 31 nM), as well as two non-selective nanomolar HDAC inhibitors (7b and 8b). The influence of linker chemistry of synthesized inhibitors on HDAC6 potency was studied using structure-based molecular modelling. The breast cancer cell-lines (MDA-MB-231 and MCF-7) were used to evaluate compound mediated in vitro anti-cancer, anti-migratory, and anti-invasive activities, leading to 8b as the most promising compound. In our study, 8b is identified as the HDAC inhibitor with very potent anti-angiogenic, anti-metastatic and anti-tumor effects in zebrafish MDA-MB-231 xenograft models at low micromolar concentrations.

Correlating basal gene expression across chemical sensitivity data to screen for novel synergistic interactors of HDAC inhibitors in pancreatic carcinoma

“…19,30 In experimental analysis we have used ROCK1/2 inhibitor RKI-1447 (abbreviated as RKI, IC 50 (ROCK1) = 14.5 nM, and IC 50 (ROCK2) = 6.2 nM), and our recently developed set of HDAC inhibitors: Compound C6 (IC 50 (HDAC1) = 4.73 μM, IC 50 (HDAC3) = 1.86 μM, IC 50 (HDAC6) = 0.19 μM, IC 50 (HDAC8) = 2.44 μM); Compound C8 (IC 50 (HDAC1) = 0.41 μM, IC 50 (HDAC3) = 0.21 μM, IC 50 (HDAC6) = 0.12 μM, IC 50 (HDAC8) = 0.24 μM); Compound C9 (IC 50 (HDAC1) = 1.47 μM, IC 50 (HDAC3) = 3.47 μM, IC 50 (HDAC6) = 0.03 μM, IC 50 (HDAC8) = 0.71 μM). 31…”