Zinc-dependent Deacetylase (HDAC) Inhibitors with Different Zinc Binding Groups

Abstract

The state of histone acetylation plays a very crucial role in carcinogenesis and its development by chromatin remodeling and thus altering transcription of oncogenes and tumor suppressor genes. Such epigenetic regulation was controlled by zinc-dependent histone deacetylases (HDACs), one of the major regulators. Due to the therapeutic potential of HDACs as one of the promising drug targets in cancer, HDAC inhibitors have been intensively investigated over the last few decades. Notably, there are five HDAC inhibitors already approved to the market. Vorinostat (SAHA), Belinostat (PXD-101) and Romidepsin (FK228) have been approved by Food and Drug Administration (FDA) in USA for treating cutaneous T-cell lymphoma (CTCL) or peripheral T cell lymphoma (PTCL) while Panbinostat (LBH-589) has also been approved by the FDA for the treatment of multiple myeloma. Recently, Chidamide was approved by China Food and Drug Administration (CFDA) for the treatment of PTCL. The structural feature of almost all HDAC inhibitors consists of Cap group, linker, and zinc-binding group (ZBG). The binding of ZBG groups to zinc ion plays a decisive role in the inhibition of HDAC. Therefore, we will summarize the developed HDAC inhibitors according to different ZBG groups and discuss their binding mode with zinc ion.

Non-Cell-Autonomous Regulation of Optic Nerve Regeneration by Amacrine Cells

“…Chelation of Zn 2+ after ONC can potentially inhibit histone deacetylases (HDACs), enzymes that deacetylate histone proteins, thereby rendering chromatin more accessible for transcription. The deacetylating activity of HDACs depends on the binding of Zn 2+ in the HDAC active site pocket (Pelzel et al, 2010;Li et al, 2019). Prevention of histone deacetylation by inhibition of HDAC activity caused by removal of Zn 2+ from HDACs can potentially facilitate transcription of activity-dependent genes and ultimately add to the effects of RGC activation.…”

Role of Histone Deacetylases in Carcinogenesis: Potential Role in Cholangiocarcinoma

“…HDAC classes I, II, and IV require a zinc molecule (Zn +2 ) as a cofactor in their active site. As a result, the Zn 2+ binding HDACis can inhibit these HDACs [8], whereas sirtuins (SIRTs), a class III HDAC, require NAD + as a cofactor rather than Zn 2+ , and are homologous to Sir2 protein in yeast, with similar functions. As a result, Zn +2 -binding HDACis cannot inhibit class III HDACs (Table 2) [9].…”

“…travel between the cytoplasm and nucleus and are larger than the other two Zn +2 -dependent classes of HDACs, on the basis of domain organization and sequence. HDAC class II is further subdivided into class IIa (HDACs 4, 5, 7, and 9) and class IIb (HDACs 6 and 8), with the latter being characterized as having two deacetylase domains [8]. Class IV has only one HDAC member (HDAC11) [11].…”

Selective Targeting of Epigenetic Readers and Histone Deacetylases in Autoimmune and Inflammatory Diseases: Recent Advances and Future Perspectives

“…In addition, HDAC inhibitors (HDACi) and BET protein inhibitors (I-BET) have shown strong efficacy in preclinical models of several inflammatory and autoimmune diseases, such as models of inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Although several epigenetic inhibitors are being investigated in human trials, relatively few have progressed into clinical practice and thus far exclusively in the cancer field, largely due to the toxicity profile of these compounds [ 17 , 27 ]. Since these first-generation inhibitors typically target multiple members of the HDAC or BET family, unwanted effects may be linked to a broad impact on transcriptional activity that extends to off-target pathways [ 28 , 29 ].…”