Review articleHDAC as onco target: Reviewing the synthetic approaches with SAR study of their inhibitors
Graphical abstract
Introduction
After years of research, the researchers developed a deep-seated knowledge that cancer occurs because of aggressive mutations that occur in the human genome. The supremacy of oncogenes and the suppression of tumor suppressing genes have always been the prime factor in cancer. Pathophysiology of cancer involves genetic factors, metastasis and epigenetic factors. Genetic factors include the heavy emergence of oncogenes and suppression of tumor suppressor genes which may be attributed to mutations that occur as a result of exposure to various carcinogens that may be chemically induced or physically induced. Other than genetic factors, the important one is the epigenetic modifications that involve modifications except the gene mutations. In other words, epigenetic modifications are the one that does not involve any change in nucleotide sequence. They include DNA hypo- and hyper-methylation, modifications in the histone protein and changes in chromosomal framework caused by indecorous expression of certain proteins. Histone proteins can undergo a variety of changes some of which include formylation, methylation, acetylation, phosphorylation, propionylation, butyrylation, hydroxylation etc. Apart from these modifications, a family of HDACs is involved in regulation of chromatin structure and function.
The epigenetic modification not only alter the interaction of the histone with DNA but also affects the ability of chromatin associated complexes to deal with the proof reading mechanism thereby losing their ability to control cell growth and differentiation, so epigenetic modifications like genetic changes can act as drivers for cancer onset and development.
Numerous efforts have been made to synthesize effective anticancer drugs but resistance to the type of chemotherapy employed leads to failure of treatment. Epigenetic changes may be considered as a part consequence of chemo-resistance which leads to failure to treatment of genetic mutations and metastasis. The development of drugs that prevent these epigenetic changes had provided a deep insight into anticancer drug research. One such class of drugs that inhibit a type of epigenetic change is the histone deacetylase inhibitor, which prevents the deacetylation of histone by inhibiting the enzyme histone deacetylase [1]. HATs and HDACs are the class of enzymes that regulate acetylation and deacetylation of the histone proteins (Scheme 1) [2]. The amount of histone acetylation governed by HDAC and HAT (Histone acetyl transferase) along with the post-translational modifications defines a gene code that is identified by the proteins other than the histone proteins involved in the regulation of gene expression. HDACs are also involved in the acetylation of some non-histone proteins such as p53 and other transcription factors which shall be discussed later in the review [3].
HDACs are also involved in a number of other biological pathways such as cellular signal transduction, cellular growth, death and various types of cancer mainly myeloid leukemia [4,5]. It can be said that the levels of lysine residue acetylations of histone 3 and 4 are controlled by the balanced activities of HDAC and HAT on the histone proteins [6]. These are seen in early tumorogenesis which proves the deacetylation and demethylation of the residues (especially the lysine residues) of the histone H4 as the main feature in cancer development [7].
The mechanism underlying histone hypoacetylation in cancer is not known but the hypothesis produced by various researcher states that it is due to the laziness of HATs to acetylate the lysine residues due to impaired DNA or chromosomal dislocations or due to hyper handwork of HDACs [8]. It had been seen that, under stress conditions, tumor suppressor p53 is acetylated both in-vitro and in-vivo by HDAC1 which indicating them to be the key regulators in normal cellular functions and as promising targets for the treatment of malignancies inspiring the researchers to develop anti-HDACs [9].
Even after twenty years of synthetic efforts, only 4 new molecules have been approved by FDA as HDAC inhibitors. Some are still on the urge to leave behind the clinical trials and become epigenetic drug candidates that can be either used as a main drug or an adjuvant with the existing potent anti-cancer drugs to further improve their potency. Valproic acid known for its anti-epileptic activity was tested for its HDAC inhibition due to the known pharmacological profile of the drug. This further increased the curiosity of the researchers and led to the discovery of the first FDA clinically approved drug Vorinostat otherwise known as SAHA i.e., suberoylanilide hydroxamide, added on by another cyclic peptide called Romidepsin. This was followed by Belinostat and Panabinostat. Even though the success of HDAC inhibitors is celebrated for leukemias, they are still a failure in case of solid tumors.
It can be expected that the next generation HDAC inhibitors will provide a light on the required improvements taking into consideration they are delivered in an optimized way. In this review, we mainly pivot on brief knowledge of biological of HDAC and chemistry of presently available HDAC inhibitors, inhibitors in clinical trial and available synthetic schemes with SAR study of several emerging HDAC inhibitors which categorize on the basis of their structure modification such as with modified cap group, linker and different zinc binding groups. Prior to these, we gave some fundamental information in the epigenetic biology of HDACs since the basics of how things work in case of HDACs had to be first recalled.
Section snippets
Classification of HDACs
Till date, eighteen types of human HDAC enzymes have been identified and they are classified into four groups based on their similarity with yeast HDACs. Out of all the classes of HDAC enzyme known, class I, II, and IV HDAC enzymes are metallo-enzymes (zinc dependent) that require zinc metal ion for pronouncing biological activity [[10](b), [10], [10](a)].
SAR study of hydroxamic acid derivatives
SAHA inhibits most of the 11 metal dependent HDAC isoforms. Nonspecific inhibition may account for several mild to severe side effects associated with treatment, including dehydration, thrombocytopenia, anorexia and cardiac arrhythmia. Due to the continual use and side effects associated with HDACi, there has been developing concern for minimizing the side effects by modifying the cap group by using benzimidazole, purine, pyrimidine, lactam and linker such as substituted aliphatic, triazole,
Dual targeting HDAC inhibitors
Hybrid molecules are described as a chemical entity with two (or more than two) pharmacophores which works on disparate or same biological functions or targets via diverse approach. These are designed to optimize biological properties like affinity and selectivity. Due to its advanced mode of action and high selectivity, the hybrid molecules based chemotherapy emerges as a beneficial tool in contemporary trend of anticancer drug discovery [327].
Single target agents can perform excellent during
Natural HDAC inhibitors
Bioactive natural pharmacophores are serendipitous drug candidates, which prompt synthetic strategies for enhancing, improving and helping the drug research and development. It has been found that natural HDAC inhibitors have surfaced as one of the most successful HDAC inhibitors [[356](a), [356](b), [356]]. The exploration of naturally present HDACi has contributed intensely potent inhibition of the deacetylase enzymes. On the basis of structural features, the known natural HDACi are divided
Summary and outlooks
The present review covers the focal points of HDAC inhibitors derivatives as a template for the exploration and advancement of anticancer agents. In recent years much attention has been focused on HDAC, metalloenzyme of multicomponent structure, as one of various cancer specific targets tested. Activities of HDACs have been seen to be regulated on multiple levels, including protein-protein interactions, post-translational modifications (sumoylation, phosphorylation and proteolysis), subcellular
Acknowledgements
Rekha Sangwan highly acknowledges Council of Scientific and Industrial Research (CSIR) for Senior Research Fellowship. Author gratefully acknowledges financial support by Department of Science and Technology (DST), India. This is CDRI communication no 9738.
References (385)
- et al.
Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis
J. Mol. Biol.
(2004) - et al.
Histone deacetylase 1 and 2 in mesenchymal tumors
Mod. Pathol.
(2012) - et al.
HDAC inhibitor-based therapies: can we interpret the code
Molecular Oncology
(2012)et al.Histone deacetylases (HDACs): characterization of the classical HDAC family
Biochem. J.
(2003) - et al.
Kinetic and structural insights into the binding of histone deacetylase 1 and 2 (HDAC1, 2) inhibitors
Bioorg. Med. Chem.
(2016) - et al.
On the function of the 14 Å long internal cavity of histone deacetylase-like protein: implications for the design of histone deacetylase inhibitors
J. Med. Chem.
(2004) - et al.
HDAC4 represses vascular endothelial growth factor expression in chondrosarcoma by modulating RUNX2 activity
J. Biol. Chem.
(2009) - et al.
Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis
Cell
(2004) - et al.
Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth and contractility
Genes Dev.
(2007) - et al.
HDAC7, a thymus-specific class II histone deacetylase, regulates Nur77 transcription and TCR-mediated apoptosis
Immunity
(2003) - et al.
Structural insights into HDA C6 tubulin deacetylation and its selective inhibition
Nat. Chem. Biol.
(2016)
Histone deacetylase 6 structure and molecular basis of catalysis and inhibition
Nat. Chem. Biol.
Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors
Leukemia
SIRT1 is significantly elevated in mouse and human prostate cancer
Canc. Res.
HDAC11 plays an essential role in regulating OX40 ligand expression in Hodgkin lymphoma
Blood
Regulation of histone deacetylase activities
J. Cell. Biochem.
Histone deacetylase inhibitors: molecular mechanism of action
Oncogene
Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization
Proc. Natl. Acad. Sci. Unit. States Am.
Role of the tetradecapeptide repeat domain of human histone deacetylase 6 in cytoplasmic retention
J. Biol. Chem.
Histone deacetylases and cancer
Molecular Oncology
The dual role of sirtuins in cancer
Genes Cancer
Deacetylation of nonhistone proteins by HDACs and the implications in cancer
Handb. Exp. Pharmacol.
Multiple roles of class I HDACs in proliferation, differentiation, and development
Cell. Mol. Life Sci.
Activation of p53 sequence- specific DNA binding by acetylation of the p53 C-terminal domain
Cell
Regulation of E2F1 activity by acetylation
EMBO J.
Duration of nuclear NF-kappaB action regulated by reversible acetylation
Science
Stat3 dimerization regulated by reversible acetylation of a single lysine residue
Science
The balance between acetylation and deacetylation controls Smad7 stability
J. Biol. Chem.
Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis
Mol. Cell.
Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors
Nature
Theoretical study revealing the functioning of a novel combination of catalytic motifs in histone deacetylase
Bioorg. Med. Chem.
Unexpected deacetylation mechanism suggested by a density functional theory QM/MM Study of histone-deacetylase-like protein
J. Am. Chem. Soc.
Structural and functional analysis of the human Hdac4 catalytic domain reveals a regulatory zinc-binding domain
J. Biol. Chem.
A New amidohydrolase from Bordetella or Alcaligenes strain FB188 with similarities to histone deacetylases
J. Bacteriol.
Human HDAC7 harbors a class IIa histone deacetylase-specific zinc binding motif and cryptic deacetylase activity
J. Biol. Chem.
Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer
Nat. Genet.
Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines
Mol. Canc. Therapeut.
Histone deacetylase inhibitors: molecular mechanisms of action
Oncogene
DFT-based ranking of zinc-binding groups in histone deacetylase inhibitors
Bioorg. Med. Chem.
Development of histone deacetylase inhibitors for cancer treatment
Expet Rev. Anticancer Ther.
Lysine acetylation targets protein complexes and co-regulates major cellular functions
Science
Overlapping functions of Hdac1 and Hdac2 in cell cycle regulation and haematopoiesis
EMBO J.
Anticancer activities of histone deacetylase inhibitors
Nat. Rev. Drug Discov.
Histone deacetylases and cancer: causes and therapies
Nat. Rev. Canc.
Histone modifications and chromatin dynamics: a focus on filamentous fungi
FEMS Microbiol. Rev.
The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men
Nat. Rev. Mol. Cell Biol.
Histone deacetylases (HDACs): characterization of the classical HDAC family
Biochem. J.
Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility
Genes Dev.
HDAC2 overexpression confers oncogenic potential to human lung cancer cells by deregulating expression of apoptosis and cell cycle proteins
J. Cell. Biochem.
Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor
Proc. Natl. Acad. Sci. Unit. States Am.
Structure of a histone deacetylase homologue bound to trichostatin A
Nature
Mutagenesis studies of the 14 Å internal cavity of histone deacetylase 1: insights toward the acetate-escape hypothesis and selective inhibitor design
J. Med. Chem.
Exploration of the HDAC2 foot pocket: synthesis and SAR of substituted N-(2-aminophenyl)benzamides
Bioorg. Med. Chem. Lett
Histone deacetylase (HDAC) inhibitor kinetic rate constants correlate with cellular histone acetylation but not transcription and cell viability
J. Biol. Chem.
Toward selective histone deacetylase inhibitor design: homology modeling, docking studies, and molecular dynamics simulations of human class I histone deacetylases
J. Med. Chem.
On the function of the internal cavity of histone deacetylase protein 8: R37 is a crucial residue for catalysis
Bioorg. Med. Chem. Lett
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