Gamze BORA, Suat SARI, Hayat ERDEM YURTER, Gülce TAŞKOR, Sevim DALKARA

Class I histone deacetylase inhibition by aryl butenoic acid derivatives: In silico and in vitro studies

ABSTRACT: Histone deacetylases (HDAC) are evolutionary conserved enzymes, which catalyze removal of acetylgroups from histone and non-histone proteins, therefore, control multiple biological processes. Inhibition of theiractivities have been investigated to modify gene expression and/or protein functions not only for treatment of certaindiseases but also for understanding functions of deacetylase isoforms. We previously synthesized aryl butenoic acidderivatives and identified their pan-HDAC inhibition activities. In this study, we investigated selective inhibitionactivities of these derivatives (C1, C3, C4) on class I HDACs using in silico and in vitro approaches. Molecular dockingstudies of the three aryl butenoic acid derivatives were performed on the crystal structures of HDAC 1, 2, 3 and 8, whichwere obtained from RCSB protein databank, using Glide software. In vitro inhibition activities of the compounds at twodifferent concentrations were tested using fluorometric assay. In silico results indicated that all the compounds showedhigher affinity to HDAC 1 and 8 than other class I deacetylases. In vitro analysis showed that the compounds inhibitHDAC 8 more effectively than HDAC 1. It was shown that C1 had higher binding affinity and inhibition activity to bothenzymes. We concluded that, C1 inhibited both HDAC 1 and 8, however, C3 and C4 showed slight selectivity for HDAC8 over HDAC 1, which was in agreement with the docking studies. Further cell culture studies will be valuable todetermine increased acetylation on target proteins in response to compound treatment.

PDF

___

[1] Strahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000; 403(6765): 41-45. [CrossRef]
[2] Nicholson TB, Veland N, Chen T. Writers, Readers, and Erasers of Epigenetic Marks. In: Gray SG. Epigenetic cancer therapy, first ed., Academic Press, Elsevier, 2015, pp. 31-66
[3] Seto E, Yoshida M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb Perspect Biol. 2014; 6(4): a018713: 1-26. [CrossRef]
[4] Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011; 21(3): 381-395. [CrossRef]
[5] De Ruijter AJ, Van Gennip AH, Caron HN, Kemp S, Van Kuilenburg AB. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. 2003; 370: 737-749. [CrossRef]
[6] Fischle W, Dequiedt F, Hendzel MJ, Guenther MG, Lazar MA, Voelter W, Verdin E. Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR. Mol Cell. 2002; 9(1): 45-57. [CrossRef]
[7] Morris MJ, Monteggia LM. Unique functional roles for class I and class II histone deacetylases in central nervous system development and function. Int J Dev Neurosci. 2013; 31(6): 370-381. [CrossRef]
[8] Thomas EA, D'Mello SR. Complex neuroprotective and neurotoxic effects of histone deacetylases. J Neurochem. 2018; 145(2): 96-110. [CrossRef]
[9] Didonna A, Opal P. The promise and perils of HDAC inhibitors in neurodegeneration. Ann Clin Transl Neurol. 2015; 2(1): 79-101. [CrossRef]
[10] Jia H, Morris CD, Williams RM, Loring JF, Thomas EA. HDAC inhibition impairs beneficial transgenerational effects in Huntington’s disease mice via altered DNA and histone methylation. Proc Natl Acad Sci U S A. 2015; 6; 112(1): E56-64. [CrossRef]
[11] Yang SS, Zhang R, Wang G, Zhang YF. The development prospection of HDAC inhibitors as a potential therapeutic direction in Alzheimer’s disease. Transl Neurodegener. 2017; 6 (19): 1-6. [CrossRef]
[12] Lai JI, Leman LJ, Ku S, Vickers CJ, Olsen CA, Montero A, Ghadiri MR, Gottesfeld JM. Cyclic tetrapeptide HDAC inhibitors as potential therapeutics for spinal muscular atrophy: screening with IPSC-derived neuronal cells. Bioorg Med Chem Lett. 2017; 27(15): 3289-3293. [CrossRef]
[13] Lazo-Gómez R, Ramírez-Jarquín UN, Tovar-Y-Romo LB, Tapia R. Histone deacetylases and their role in motor neuron degeneration. Front Cell Neurosci. 2013; 7: 243, 1-7. [CrossRef]
[14] Jones PA, Issa JP, Baylin S. Targeting the cancer epigenome for therapy. Nat Rev Genet. 2016; 17(10): 630-641. [CrossRef]
[15] Bora-Tatar G, Erdem-Yurter H. Investigations of curcumin and resveratrol on neurite outgrowth: perpectives on spinal muscular atrophy. Biomed Res Int. 2014; 709108: 1-8. [CrossRef]
[16] Lunke S, El-Osta A. Applicability of histone deacetylase inhibition for the treatment of spinal muscular atrophy. Neurotherapeutics. 2013; 10(4): 677-687. [CrossRef]
[17] Abend A, Kehat I. Histone deacetylases as therapeutic targets: from cancer to cardiac disease. Pharmacol Ther. 2015; 147: 55-62. [CrossRef]
[18] Manal M, Chandrasekar MJ, Gomathi Priya J, Nanjan MJ. Inhibitors of histone deacetylase as antitumor agents: A critical review. Bioorg Chem. 2016; 67: 18-42. [CrossRef]
[19] Suraweera A, O'Byrne KJ, Richard DJ. Combination therapy with histone deacetylase inhibitors (HDACi) for treatment of cancer: Achieving the full potential of HDACi. Front Oncol. 2018; 8(92): 1-15. [CrossRef]
[20] Mehnert JM, Kelly WK. Histone deacetylase inhibitors: Biology and mechanism of action. Cancer J. 2007; 13(1): 23- 29. [CrossRef]
[21] Esiyok PA, Seven O, Eymur G, Bora-Tatar G, Dayangaç-Erden D, Yelekci K, Yurter H, Demir AS. Aryl butenoic acid derivatives as a new class of histone deacetylase inhibitors: synthesis, in vitro evaluation, and molecular docking studies. Turk J Chem. 2014; 38(2): 338-344. [CrossRef]
[22] Türk Patent ve Marka Kurumu, Patent başvuru numarası: 2011/03844, Buluş başlığı; Aril bütanoik asit türevleri, bunların HDAC inhibitör aktiviteleri ve gen ekspresyonunu arttırıcı özellikleri. http://online.turkpatent.gov.tr/EPATENT/servlet/PreSearchRequestManager
[23] Watson PJ, Millard CJ, Riley AM, Robertson NS, Wright LC, Godage HY, Cowley SM, Jamieson AG, Potter BV, Schwabe JW. Insights into the activation mechanism of class I HDAC complexes by inositol phosphates. Nat Commun. 2016; 25(7): 11262. [CrossRef]
[24] Lombardi PM, Cole KE, Dowling DP, Christianson DW. Structure, mechanism, and inhibition of histone deacetylases and related metalloenzymes. Curr Opin Struct Biol. 2011; 21(6): 735-743. [CrossRef]
[25] Uba AI, Yelekçi K. Identification of potential isoform-selective histone deacetylase inhibitors for cancer therapy: a combined approach of structure-based virtual screening, ADMET prediction and molecular dynamics simulation assay. J Biomol Struct Dyn. 2018; 36(12): 3231-3245. [CrossRef]
[26] Hsu KC, Liu CY, Lin TE, Hsieh JH, Sung TY, Tseng HJ, Yang JM, Huang WJ. Novel class IIaselective histone deacetylase ınhibitors discovered using an in silico virtual screening approach. Sci Rep. 2017; 7: 3228. [CrossRef]
[27] Ingham OJ, Paranal RM, Smith WB, Escobar RA, Yueh H, Synder T, Porco JA Jr, Bradner JE, Beeler AB. Development of a potent and selective HDAC8 inhibitor. ACS Med Chem Lett. 2016; 7(10): 929-932. [CrossRef]
[28] Noor Z, Afzal N, Rashid S. Exploration of novel inhibitors for class I histone deacetylase isoforms by QSAR Modeling and Molecular Dynamics Simulation Assay. PLoS One. 2015; 10(11): e0143155. [CrossRef]
[29] Bora-Tatar G, Dayangaç-Erden D, Demir AS, Dalkara S, Yelekçi K, Erdem-Yurter H. Molecular modifications on carboxylic acid derivatives as potent histone deacetylase inhibitors: activity and docking studies. Bioorg Med Chem. 2009; 17(14): 5219-5228. [CrossRef]
[30] Mithraprabhu S, Kalff A, Chow A, Khong T, Spencer A. Dysregulated Class I histone deacetylases are indicators of poor prognosis in multiple myeloma. Epigenetics. 2014; 9(11): 1511-1520. [CrossRef]
[31] Yoon S, Eom GH. HDAC and HDAC Inhibitor: From Cancer to Cardiovascular Diseases. Chonnam Med J. 2016; 52(1): 1–11. [CrossRef]
[32] Banks JL, Beard HS, Cao Y, Cho AE, Damm W, Farid R, Felts AK, Halgren TA, Mainz DT, Maple JR, Murphy R, Philipp DM, Repasky MP, Zhang LY, Berne BJ, Friesner RA, Gallicchio E, Levy RM. Integrated modeling program, applied chemical theory (IMPACT). J Comput Chem. 2005; 26(16): 1752-1780. [CrossRef]
[33] Lauffer BE, Mintzer R, Fong R, Mukund S, Tam C, Zilberleyb I, Flicke B, Ritscher A, Fedorowicz G, Vallero R, Ortwine DF, Gunzner J, Modrusan Z, Neumann L, Koth CM, Lupardus PJ, Kaminker JS, Heise CE, Steiner P. Histone deacetylase (HDAC) inhibitor kinetic rate constants correlate with cellular histone acetylation but not transcription and cell viability. J Biol Chem. 2013; 288(37): 26926-26943. [CrossRef]
[34] Watson PJ, Fairall L, Santos GM, Schwabe JW. Structure of HDAC3 bound to co-repressor and inositol tetraphosphate. Nature. 2012; 481(7381): 335-340. [CrossRef]
[35] Tabackman AA, Frankson R, Marsan ES, Perry K, Cole KE. Structure of 'linkerless' hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket. J Struct Biol. 2016; 195(3): 373-378. [CrossRef]
[36] Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE. The Protein Data Bank. Nucleic Acids Res. 2000; 28(1): 235-242. [CrossRef]
[37] Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des. 2013; 27(3): 221-234. [CrossRef]
[38] Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, Francis P, Shenkin PS. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem. 2004; 47(7): 1739-1749. [CrossRef]
[39] Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, Banks JL. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem. 2004; 47(7): 1750-1759. [CrossRef]
[40] Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem. 2006; 49(21): 6177-6196. [CrossRef]