Preferential HDAC6 inhibitors derived from HPOB exhibit synergistic antileukemia activity in combination with decitabine.

Histone deacetylase 6 (HDAC6) is an emerging drug target to treat oncological and non-oncological conditions. Since highly selective HDAC6 inhibitors display limited anticancer activity when used as single agent, they usually require combination therapies with other chemotherapeutics. In this work, we synthesized a mini library of analogues of the preferential HDAC6 inhibitor HPOB in only two steps via an Ugi four-component reaction as the key step. Biochemical HDAC inhibition and cell viability assays led to the identification of 1g (highest antileukemic activity) and 2b (highest HDAC6 inhibition) as hit compounds. In subsequent combination screens, both 1g and especially 2b showed synergy with DNA methyltransferase inhibitor decitabine in acute myeloid leukemia (AML). Our findings highlight the potential of combining HDAC6 inhibitors with DNA methyltransferase inhibitors as a strategy to improve AML treatment outcomes.

Synthesis and structure-activity relationships of pyrazole-based inhibitors of meprin α and ß.

Targeting metalloproteinases has been in the focus of drug design for a long time. However, meprin α and ß emerged as potential drug targets just recently and are linked to several diseases with different pathological background. Nevertheless, the validation of meprins as suitable drug targets still requires highly potent and selective inhibitors as chemical probes to elucidate their role in pathophysiology. Albeit highly selective inhibitors of meprin ß have already been reported, only inhibitors of meprin α with modest activity or selectivity are known. Starting from recently reported heteroaromatic scaffolds, the aim of this study was the optimisation of meprin α and/or meprin ß inhibition while keeping the favourable off-target inhibition profile over other metalloproteases. We report potent pan-meprin inhibitors as well as highly active inhibitors of meprin α with superior selectivity over meprin ß. The latter are suitable to serve as chemical probes and enable further target validation.

Heteroaromatic Inhibitors of the Astacin Proteinases Meprin α, Meprin ß and Ovastacin Discovered by a Scaffold-Hopping Approach.

Astacin metalloproteinases, in particular meprins α and ß, as well as ovastacin, are emerging drug targets. Drug-discovery efforts have led to the development of the first potent and selective inhibitors in the last few years. However, the most recent compounds are based on a highly flexible tertiary amine scaffold that could cause metabolic liabilities or decreased potency due to the entropic penalty upon binding to the target. Thus, the aim of this study was to discover novel conformationally constrained scaffolds as starting points for further inhibitor optimization. Shifting from flexible tertiary amines to rigid heteroaromatic cores resulted in a boost in inhibitory activity. Moreover, some compounds already exhibited higher activity against individual astacin proteinases compared to recently reported inhibitors and also a favorable off-target selectivity profile, thus qualifying them as very suitable chemical probes for target validation.

A Primary Evaluation of Potential Small-Molecule Inhibitors of the Astacin Metalloproteinase Ovastacin, a Novel Drug Target in Female Infertility Treatment.

Despite huge progress in hormonal therapy and improved in vitro fertilization methods, the success rates in infertility treatment are still limited. A recently discovered mechanism revealed the interplay between the plasma protein fetuin-B and the cortical granule-based proteinase ovastacin to be a novel key mechanism in the regulation of fertilization. Upon sperm-egg fusion, cleavage of a distinct zona pellucida component by ovastacin destroys the sperm receptor, enhances zona robustness, and eventually provides a definitive block against polyspermy. An untimely onset of this zona hardening prior to fertilization would consequently result in infertility. Physiologically, this process is controlled by fetuin-B, an endogenous ovastacin inhibitor. Here we aimed to discover small-molecule inhibitors of ovastacin that could mimic the effect of fetuin-B. These compounds could be useful lead structures for the development of specific ovastacin inhibitors that can be used in infertility treatment or in vitro fertilization.

Tertiary-Amine-Based Inhibitors of the Astacin Protease Meprin†α.

Metalloproteinases of the astacin family are drawing ever increasing attention as potential drug targets. However, knowledge regarding inhibitors thereof is limited in most cases. Crucial for the development of metalloprotease inhibitors is high selectivity, to avoid side effects brought about by inhibition of off-target proteases and interference with physiological pathways. In this study we aimed at the design of novel selective inhibitors for the astacin proteinase meprin α. Based on a recently identified tertiary amine scaffold, a series of compounds was synthesized and evaluated. The compounds exhibit reasonable inhibitory activity with high selectivity over other metalloproteases. The isoenzyme meprinâ€…ß is only slightly inhibited. Hence, the present study revealed a novel class of selective meprin α inhibitors with improved selectivity over known compounds.