Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet, the currently FDA-approved HDAC inhibitors non-specifically target at least several of the eleven structurally similar but functionally different HDAC isozymes, which hampers their broad usage in clinical settings.Selective inhibitors targeting single HDAC isozymes are being developed, but precise understanding in molecular terms of their selectivity remains sparse. Here, we show that HDAC8-selective inhibitors adopt a L-shaped conformation required for their binding to a HDAC8-specific pocket formed by HDAC8 catalytic tyrosine and HDAC8 L1 and L6 loops. In other HDAC isozymes, a L1-L6 lock sterically prevents L-shaped inhibitor binding. Shielding of the HDAC8-specific pocket by protein engineering decreases potency of HDAC8-selective inhibitors and affects catalytic activity. Collectively, our results unravel key HDAC8 active site structural and functional determinants important for the design of nextgeneration chemical probes and epigenetic drugs.
We
herein report the conventional and microscale parallel synthesis
of selective inhibitors of human blood coagulation factor XIIa and
thrombin exhibiting a 1,2,4-triazol-5-amine scaffold. Structural variations
of this scaffold allowed identifying derivative 21i,
a potent 29 nM inhibitor of FXIIa, with improved selectivity over
other tested serine proteases and also finding compound 21m with 27 nM inhibitory activity toward thrombin. For the first time,
acylated 1,2,4-triazol-5-amines were proved to have anticoagulant
properties and the ability to affect thrombin- and cancer-cell-induced
platelet aggregation. Performed mass spectrometric analysis and molecular
modeling allowed us to discover previously unknown interactions between
the synthesized inhibitors and the active site of FXIIa, which uncovered
the mechanistic details of FXIIa inhibition. Synthesized compounds
represent a promising starting point for the development of novel
antithrombotic drugs or chemical tools for studying the role of FXIIa
and thrombin in physiological and pathological processes.
The Zn-dependent deacetylase LpxC is an essential enzyme of lipid A biosynthesis in Gram-negative bacteria and a promising target for the development of antibiotics selectively combating Gram-negative pathogens. Researchers from industry and academia have synthesized structurally diverse LpxC inhibitors, exhibiting different LpxC inhibitory and antibacterial activities. Areas covered: A brief introduction into the structure and function of LpxC, showing its suitability as antibacterial target, along with the structures of several reported LpxC inhibitors, is given. The article reviews patents (reported between 2010 and 2016) and related research publications on novel small-molecule LpxC inhibitors. Emphasis is placed on structure-activity relationships within the reported series of LpxC inhibitors. Expert opinion: The performed analysis of patents revealed that the current search for novel LpxC inhibitors is focused on small molecules, sharing common structural features like a Zn-chelating group as well as a highly lipophilic side-chain. However, despite the promising preclinical data of many of the reported compounds, besides the recently withdrawn clinical candidate ACHN-975, no other LpxC inhibitor has entered clinical trials. The lack of clinical candidates might be related with undesired effects caused by the common structural elements of the LpxC inhibitors.
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