Potent, Selective, and CNS-Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors

Abstract

Potent and selective class IIa HDAC tetrasubstituted cyclopropane hydroxamic acid inhibitors were identified with high oral bioavailability that exhibited good brain and muscle exposure. Compound 14 displayed suitable properties for assessment of the impact of class IIa HDAC catalytic site inhibition in preclinical disease models.KEYWORDS: Class IIa HDAC inhibitors, hydroxamic acid, CNS exposure, tetrasubstituted cyclopropane, cyclopropanation, Huntington's disease I nhibition of class IIa HDAC enzymes has been suggested as a therapeutic strategy for a number of indications, including Huntington's disease (HD) and muscular atrophy. Class IIa HDACs are large proteins with multiple functions including transcription factor binding and N-acetyl lysine recognition. 1,2 Of most interest to our laboratory is the role of class IIa HDAC biology in HD, in particular the beneficial effect, which has been observed following HDAC4 genetic suppression. 3−5 Replication of these effects in preclinical models of HD via occupancy of the class IIa HDAC catalytic domain would provide a rationale for small molecule therapy. Currently there are no marketed HDAC class IIa-selective inhibitors, whereas four pan-HDAC inhibitors, vorinostat (SAHA), romidepsin, belinostat, and panobinostat are on the market.Class IIa-selective HDAC inhibitors would represent important tools for elucidating the therapeutic potential of this protein family. We recently reported the structure-based design of trisubstituted cyclopropane class IIa-selective HDAC inhibitors as potential therapeutics in HD. 6 This improved selectivity was driven by exploiting a selectivity pocket ( Figure 1, shown with compound 13) that is not present in the class I HDAC isoforms. This pocket is formed as a consequence of a tyrosine-histidine substitution. 7 We now report the discovery of tetrasubstituted cyclopropane hydroxamic acid class IIa HDAC inhibitors, with additional substitution at C1 (Figure 1). These compounds exhibited improved pharmacokinetic profiles, and so may provide a further means for evaluating efficacy in preclinical in vivo HD disease models.

In silico Design of Novel Histone Deacetylase 4 Inhibitors: Design Guidelines for Improved Binding Affinity

“…Each cyclopropane derivative produced similar interactions within the HDAC4 receptor. A mode of binding having bidentate coordination of the Zn 2+ atom with the hydroxamate tail was produced, which is consistent with crystal structures of other hydroxamic acid HDAC inhibitors [2,21,23,24]. Similar to panobinostat, the cyclopropane derivatives were shown to be able to participate in π-π stacking interactions within the core of the active site between the residues Phe-812 and Phe-871 lining the gorge [25].…”

“…HDAC4 inhibitor compounds developed up to this point have not been shown to have any direct interaction with Asp-759 [16,21,22] which sits on the rim of the opening to the active site. This residue creates a negative-charge region that could participate in electrostatic interactions and could permit hydrogen bonding.…”

“…Heteroaromatic rings can provide opportunities for π-stacking, hydrophobic interactions, hydrogen bonding, and even electrostatic interactions. Most work on cyclopropane hydroxamic acid derivatives has utilized the phenyl ring as the main substituent to access the LSP [16,21,22]. Recent work has expanded this to rings having a single nitrogen atom [22].…”

“…Some of the trifluoromethyl ketone HDAC inhibitor derivatives developed were not shown to have decent stability [18], however, some work has been done to improve these challenges [19]. Prior work on the development of the hydroxamic acid class of HDAC4 inhibitors has focused significantly around the exploration of heteroaromatic capping moieties [16], the addition of a fluorine atom on the cyclopropane ring for enhanced binding [21], and the positioning of polar groups on the lower selectivity pocket of HDAC4 [22]. More work can be done to expand our knowledge of optimization strategies for HDAC4 inhibitors.…”

A Fluorescence‐Lifetime‐Based Binding Assay for Class IIa Histone Deacetylases

“…These findings have culminated in the currently, broadly accepted view of a mostly non‐catalytic role of class IIa HDACs . Although their function is as yet little understood, huge effort has been directed towards the development of specific HDAC class IIa inhibitors . The therapeutic indication area for HDAC class IIa inhibitors ranges from cancer to neurodegenerative diseases like Huntington's chorea .…”