Editorial
Current Medicinal Chemistry, 2017, Vol. 24, No. 37
4103
Editorial Epigenetics: A Novel Frontier For Drug Discovery Epigenetic dysregulation plays a key role in provoking cancer and neurodegenerative signalling. Among the various players regulating epigenetic gene expression, histone acetyl transferases (HATs) and histone deacetylases (HDACs) are top in the hierarchy. The antagonistic activity of these enzymes regulates the turnover of histone acetylation. Homeostasis of histone acetylation has significant role in precise regulation of transcriptional events. Alteration of acetylation homeostasis due to aberrant activity of HATs and HDACs results in transcriptional dysregulation culminating in cancer and neurodegeneration. Therapeutic intervention of HATs and HDACs with small-molecule inhibitors has shown promising results in several malignant and neurodegenerative disorders. These inhibitors reinstate acetylation homeostasis dysregulated in disease states. The marvelous effect of these inhibitors can be understood from the grim fact that four HDAC inhibitors namely vorinostat, romidepsin, belinostat and panobinostat have been approved by US FDA for treating distinct haematological malignancies including multiple myeloma. The first review by the guest editor, Dr. Shabir Ahmad Ganai, discusses the role of HDAC6 in neurodegenerative signalling. Overactivity of HDAC6 hypo-acetylates tubulin protein thereby destabilizing it and restraining neurite growth. The article also summarizes the promising effects of small-molecules targetting HDAC6 in reversing neurological complications. The defined HDAC has neuroprotective function as it plays a marked role in proteasomal degradation of those proteins whose accumulation may promote neurodegeneration HDAC6 recruits motor protein dynein and thus promotes the transport of ubiquitinated proteins to the aggresome accelerating their clearance. At the same time, HDAC6 recruits the components of autophagic machinery and triggers the autophagosomes-lysosomal union. Thus it is quite evident that HDAC6 is a double edged sword having neuroprotective function as well. Thus the author warns that during pharmacological intervention only deacetylase activity should be obstructed while leaving its neuroprotective functions intact. The second review by Richters and Prof. Koehler addresses the implications of HATs in several disorders including cancer and neurodegeneration. This article provides brief overview on the structural and functional aspects of HATs. Importantly, the authors provide comprehensive details about the small-molecule modulators of HATs, their therapeutic effects in disease models and their possible use as therapeutic agents in the field of medicine in near future. Regarding the third review directed by Prof. Günter Niegisch, the role of HDACs in the etiology of urothelial carcinoma is elaborated. The article discusses the Classical HDACs and provides clear picture regarding the HDACs which may give maximum therapeutic benefit on pharmacological intervention. While HDAC1 and HDAC2 may prove as the most promising in treating urothelial carcinoma, HDAC8 and HDAC6 may be less relevant. Some HDACs like HDAC4 require further study as their downregulation may have a role in the pathogenesis of urothelial carcinoma. The last review by Kai Cheng, Siyu Li and Chenzhong Liao deals with macrocyclic HDAC inhibitors including cyclic peptides, depsipeptides etc. The authors address the ability of HDAC inhibitors in general as potent anticancer agents and macrocyclic HDAC inhibitors, in particular, as they have the tendency of isoform selective inhibition. Furthermore, the article gives comprehensive overview regarding the recent development of macrocyclic HDAC inhibitors as anticancer agent. Moreover, the authors have extensively discussed the advantages and disadvantages of these molecules for drug development.
Shabir Ahmad Ganai Guest Editor Department of Biotechnology University of Kashmir Srinagar-190006 Jammu & Kashmir Tel: +91 1932237562 Email:
[email protected] 1875-533X/17 $58.00+.00
© 2017 Bentham Science Publishers
