Histone deacetylase 2 selective inhibitors: A versatile therapeutic strategy as next generation drug target in cancer therapy

Shetty, Manasa Gangadhar and Kapaettu, Satyamoorthy and Kampa, Babitha Sundara and Pai, Padamini B and Deaver, Renita Esther (2021) Histone deacetylase 2 selective inhibitors: A versatile therapeutic strategy as next generation drug target in cancer therapy. Pharmacological Research. pp. 1-13. ISSN 10436618

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Abstract

Acetylation and deacetylation of histone and several non-histone proteins are the two important processes amongst the different modes of epigenetic modulation that are involved in regulating cancer initiation and development. Abnormal expression of histone deacetylases (HDACs) is often reported in various types of cancers. Few pan HDAC inhibitors have been approved for use as therapeutic interventions for cancer treatment including vorinostat, belinostat and panobinostat. However, not all the HDAC isoforms are abnormally expressed in certain cancers, such as in the case of, ovarian cancer where overexpression of HDAC1-3, lung cancer where overexpression of HDAC 1 and 3 and gastric cancer where overexpression of HDAC2 is seen. Therefore, pan-inhibition of HDAC is not an efficient way to combat cancer via HDAC inhibition. Hence, isoform-selective HDAC inhibition can be one of the best therapeutic strategies in the treatment of cancer. In this context since aberrant expression of HDAC2 largely contributes to cancer progression by silencing pro-apoptotic protein expressions such as NOXA and APAF1 (caspase 9-activating proteins) and inactivation of tumor suppressor p53, HDAC2 specific inhibitors may help to develop not only the direct targets but also indirect targets that are crucial for tumor development. However, to evelop a HDAC2 specific and potent inhibitor, extensive knowledge of its structure and specific functions is essential. The present review updates details on the structural features, physiological functions, and Abbreviations: ABCB1, ATP-binding cassette sub-family B member 1; ADMET, absorption, distribution, metabolism, excretion and toxicity; AP-1, activator protein 1; APAF1, apoptotic protease activating factor 1; APC, adenomatosis polyposis coli; ARHGAP4, rho GTPase activating protein 4; ATM, Ataxia- elangiectasia-mutated; AURKA, aurora kinase A; BCP, bone cancer pain; BCRP, breast cancer resistance protein; CDK2, cyclin-dependent kinase 2; CDK4, cyclin-dependent kinase 4; CDKi, cyclin-dependent kinase inhibitor; CK2, casein kinase; CK2IIa, casein kinase IIa; CNG2, cyclic nucleotide gated channel alpha; CoREST, corepressor for element-1- silencing transcription factor; CRC, colorectal cancer; CREB, cAMP response element-binding protein; CTCF, CCCTC-binding factor; DNMT3a, DNA (cytosine-5)- methyltransferase 3a; E2F, E2 transcription factor; ECG, electrocardiography; ERK, extracellular signal-regulated kinase; EGF, epidermal growth factor; FKBP3, FKBP prolyl isomerase 3; GLUT4, glucose transporter type 4; H2AX, H2A histone family member X; HAT, histone acetyltransferase; HDAC, histone deacetylase; HIF-1α, hypoxia inducible factor 1α; H3K18, acetylation of histone H4 at the lysine-18 residue; H4K12, acetylation of histone H4 at the lysine-12 residue; HP1, heterochromatin protein; IKK-β, nuclear factor kappa-B kinase subunit beta; IL6, interleukin 6; ER, estrogen receptor; KCC2, K+-Cl- cotransporter-2; KDAC2, lysine deacetylases; KLF4, krueppel-like factor 4; LncRNA H1, long non-coding RNA H1; LRP, lipoprotein receptor-related protein; MCL-1, myeloid cell leukemia 1; MDM2, mouse double minute 2 homolog; MMP2, matrix metalloproteinase 2; MMP9, matrix metalloproteinase 9; MMP14, matrix metalloproteinase14; mTORC1, mammalian target of rapamycin complex 1; MRP, multidrug resistance protein; NF-κb, nuclear factor kappa-light-chain-enhancer of activated B cells; uRD, ucleosome remodeling deacetylase; OCT4, octamer-binding transcription factor 4; PDB, Protein data bank; DAC, pancreatic ductal adenocarcinoma; 15-PGDH, 15- hydroxyprostaglandin dehydrogenase; PELP, proline-, glutamic acid- and leucine-rich protein 1; PgP, phosphorylated glycoprotein; PGE2, prostaglandin E2; PI3K, phosphoinositide 3-kinase; PLIN1, perilipin-1; PP1, protein phosphatase 1; PPARγ, peroxisome proliferator-activated receptor gamma; PR, progesterone receptor; PTEN, phosphatase and tensin homolog; PTM, post translation modification; RNF125, ring finger protein 125; RUNX1, runt-related transcription factor; SMC, structural maintenance of chromosomes protein; SOX2, SRY-Box transcription factor 2; SREBP, sterol regulatory element-binding protein 1; SRGN, serglycin; SUMO, small ubiquitin-like modifier; TGF-β, transforming growth Factor Beta; TNFα, tumor necrosis factor alpha; TNXL1, thioredoxin like 1; TRAIL, tumor necrosis factorrelated apoptosis-inducing ligand; TSP1, thrombospondin 1; VHL, von Hippel–Lindau; VPA, valproic acid; YY1, Yin Yang 1; YAP, yes-associated protein 1; ZEB1, zinc finger E-box binding homeobox 1; ZEB2, zinc finger

Item Type: Article
Uncontrolled Keywords: Class I HDACs; Selective inhibitor; Apoptosis; Transcription factor HDAC2 ;Chemical compounds studied in this article: Vorinostat (PubChem CID: 5311) Panobinostat (PubChem CID: 6918837) Belinostat (PubChem CID: 6918638) Trichostatin A (PubChem CID: 444732) Romidepsin (PubChem CID: 535206) Valproic acid (PubChem CID: 3121) N-(2-aminophenyl) benzamide (PubChem CID: 759408) BRD4884 (PubChem CID: 71465631) 4-(acetylamino)-N-[2-amino-5-(thiophen-2-yl)
Subjects: Life Sciences > MLSC Manipal
Depositing User: KMC Library
Date Deposited: 01 Feb 2022 09:06
Last Modified: 01 Feb 2022 09:06
URI: http://eprints.manipal.edu/id/eprint/158239

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