Balancing Histone Deacetylase (HDAC) Inhibition and Druglikeness: Biological and Physicochemical Evaluation of Class I Selective HDAC Inhibitors

Herein we report the structure-activity and structure-physicochemical property relationships of a series of class I selective ortho-aminoanilides targeting the “foot-pocket” in HDAC1&2. To balance the structural benefits and the physicochemical disadvantages of these substances, we started with a set of HDACi related to tacedinaline (CI-994) and evaluated their solubility, lipophilicity (log D7.4) and inhibition of selected HDAC isoforms. Subsequently, we selected the most promising “capless” HDACi and transferred its ZBG to our previously published scaffold featuring a peptoid-based cap group. The resulting hit compound 10c (LSH-A54) showed favorable physicochemical properties and is a potent, selective HDAC1/2 inhibitor. The following evaluation of its slow binding properties revealed that LSH-A54 binds tightly to HDAC1 in an induced-fit mechanism. The potent HDAC1/2 inhibitory properties were reflected by attenuated cell migration in a modified wound healing assay and reduced cell viability in a clonogenic survival assay in selected breast cancer cell lines

Synthesis of peptoid-based class I selective histone deacetylase inhibitors with chemosensitizing properties

There is increasing evidence that histone deacetylase (HDAC) inhibitors can (re)sensitize cancer cells for chemotherapeutics via ‘epigenetic priming’. In this work, we describe the synthesis of a series of class I selective HDAC inhibitors with 2-aminoanilides as zinc-binding groups. Several of the synthesized compounds revealed potent inhibition of the class I HDAC isoforms HDAC1, 2 and/or 3 and promising antiproliferative effects in the human ovarian cancer cell line A2780 and the human squamous carcinoma cell line Cal27. Selected compounds were investigated in a cellular model of platinum resistance. In particular compound 2a revealed potent chemosensitizing properties and full reversal of cisplatin resistance in Cal27CisR cells. This effect is related to a synergistic increase in caspase 3/7 activation and induction of apoptosis. Thus, this work demonstrates that pan-HDAC inhibition or dual class I/class IIb inhibition is not required for full reversal of cisplatin resistance

Data publication: Development and Biological Evaluation of the First Highly Potent and Specific Benzamide-Based Radiotracer [¹⁸F]BA3 for Imaging of Histone Deacetylases 1 and 2 in Brain

The data publication contain: 1) Radiosynthesis data (Scheme of the synthesis module; RP-HPLC chromatograms of formulated [18F]BA3; MLC chromatograms of in vivo metabolism studies) 2) Biological data (Baseline TAC of CD-1 mice brain, biodistribution after i.v. injection of [18F]BA3) 3) Analytical data (1H, 13C, 19F NMR spectra; LC-MS chromatograms for final products

Development and Biological Evaluation of the First Highly Potent and Specific Benzamide-Based Radiotracer [18F]BA3 for Imaging of Histone Deacetylases 1 and 2 in Brain

The degree of acetylation of lysine residues on histones influences the accessibility of DNA and, furthermore, the gene expression. Histone deacetylases (HDACs) are overexpressed in various tumour diseases, resulting in the interest in HDAC inhibitors for cancer therapy. The aim of this work is the development of a novel 18F-labelled HDAC1/2-specific inhibitor with a benzamide-based zinc-binding group to visualize these enzymes in brain tumours by positron emission tomography (PET). BA3, exhibiting high inhibitory potency for HDAC1 (IC50 = 4.8 nM) and HDAC2 (IC50 = 39.9 nM), and specificity towards HDAC3 and HDAC6 (specificity ratios >230 and >2080, respectively), was selected for radiofluorination. The two-step one-pot radiosynthesis of [18F]BA3 was performed in a TRACERlab FX2 N radiosynthesizer by a nucleophilic aliphatic substitution reaction. The automated radiosynthesis of [18F]BA3 resulted in a radiochemical yield of 1%, a radiochemical purity of >96% and a molar activity between 21 and 51 GBq/µmol (n = 5, EOS). For the characterization of BA3, in vitro and in vivo experiments were carried out. The results of these pharmacological and pharmacokinetic studies indicate a suitable inhibitory potency of BA3, whereas the applicability for non-invasive imaging of HDAC1/2 by PET requires further optimization of the properties of this compound

Data publication: Development and Biological Evaluation of the First Highly Potent and Specific Benzamide-Based Radiotracer [¹⁸F]BA3 for Imaging of Histone Deacetylases 1 and 2 in Brain

The data publication contain: 1) Radiosynthesis data (Scheme of the synthesis module; RP-HPLC chromatograms of formulated [18F]BA3; MLC chromatograms of in vivo metabolism studies) 2) Biological data (Baseline TAC of CD-1 mice brain, biodistribution after i.v. injection of [18F]BA3) 3) Analytical data (1H, 13C, 19F NMR spectra; LC-MS chromatograms for final products