The study by Pigna and collaborators provides an
The study by Pigna and collaborators provides an elegant demonstration why class IIa HDAC inhibition may not be suitable to protect the neuromuscular function in ALS, consistent with a recent study that showed only a transient protection of motor performance after treatment of the same ALS model with the class II specific HDAC inhibitor MC1568 . The current study also nicely confirms 10 years old studies using the pan-HDAC inhibitor valproic Mouse EGF / Epidermal Growth Factor Protein (Fc Tag) that potently protected motor neurons, likely via class I HDACs inhibition-dependent effects, but did not prevent NMJ denervation at late stages, possibly because of class IIa HDACs inhibition-dependent effects. In the context of ALS, recent work has shown that HDAC6 inhibitors could provide interesting protection in various mouse models  and inhibitors of class I HDACs remain also interesting targets for neuronal protection, especially as HDAC1 appears as a downstream target of both FUS and TDP-43 related ALS. Future work in this area should focus on increasing selectivity of HDAC inhibitors, and ameliorate targeting of the CNS to avoid the deleterious effects of HDAC inhibition in the periphery.
Conflict of interest
Acknowledgments The authors apologize to the many researchers whose work is not specifically referenced due to space limitations. The authors are supported by Inserm, CNRS, Unistra, ANR-16-CE92-0031 (EPIFUS), ANR-16-CE16-0015 (ToFU), Alsace Alzheimer 67, France Alzheimer (AAP SM 2017 #1664), Fondation pour la recherche médicale and Axa Banque Patrimoniale research fund.
Introduction Histone deacetylases (HDACs) are key proteins that can mediate changes in nucleosome conformation. Through modifying core histones and participating in large regulatory complexes related to transcription, HDACs can regulate cell differentiation, proliferation, and survival1., 2., 3.. Generally, aberrant HDACs have significant correlation with severe diseases, especially tumors4., 5.. Therefore, HDAC inhibitors (HDACi) are well developed, and now several HDAC inhibitors (HDACis) have been approved by the FDA; SAHA and belinostat for the treatment of cutaneous T-cell lymphoma and panobinostat for the treatment of multiple myeloma. In consideration of the complexity of tumor growth, the combination therapies with HDACis also have been developed and showed great potency in cancer treatment6., 7., 8., 9.. It has been confirmed that HDACi not only sensitized tumor cells toward various cytotoxic agents, but also enhanced the antiproliferative activity of molecular targeted antitumor drugs through synergistic effects10., 11.. Based on these findings, the HDAC inhibitors related multi-target molecules were studied, and attracted great interests of chemists12., 13.. Usually, multi-target molecules have been designed to inhibit multiple cellular targets relevant to tumor growth/survival simultaneously through the combination of different drugs or the pharmacophores from them. With the combination, the pharmacokinetics can be modulated, and selectivity and antitumor potency also can be improved. Bifunctional inhibitors that dual target both HDAC and topoisomerase II (Fig. 1, 1) have been reported, along with tubulin-histone deacetylase dual inhibitors (Fig. 1, 2). CUDC-101 (Fig. 1, 3) along with multi-acting HDAC, EGFR, and HER2 inhibitor, have showed great potential in cancer treatment. However, CUDC-907 (Fig. 1, 4), which can simultaneously inhibit both HDAC and PI3K, is currently being tested in clinical trials. Although great successes have been acquired in multi-target molecules, not all molecules satisfied the need of multi-target molecule design. The structure-activity relationship of the molecules determined that the immobilization of the HDAC inhibitory function might affect concomitant interaction with the target enzyme when the molecule was bound to a corresponding protein or complex. Partial loss of biological activity has been reported in a histone deacetylase-topoisomerase I inhibitor hybrid (Fig. 1, 5). As a result of the substitution at C-10 position of SN-38 that participated in the interaction between SN-38 and topoisomerase I, the topoisomerase inhibition activity was lost, and the antiproliferative activity of the compound was also reduced.