| Reference | 1. J Hum Genet. 2016 Sep;61(9):823-30. doi: 10.1038/jhg.2016.61. Epub 2016 Jun 2.<br />
Transcript, methylation and molecular docking analyses of the effects of HDAC inhibitors, SAHA and Dacinostat, on SMN2 expression in fibroblasts of SMA patients.<br />
Mohseni J(1), Al-Najjar BO(2)(3), Wahab HA(2), Zabidi-Hussin ZA(4)(5), Sasongko TH(1)(5).<br />
Author information:<br />
(1)Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kerian Kelantan, Malaysia. (2)Pharmaceutical Design and Simulation Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Pulau Pinang, Malaysia. (3)Faculty of Pharmacy & Medical Sciences, Al-Ahliyya Amman University, Amman, Jordan. (4)Department of Pediatrics, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kerian Kelantan, Malaysia. (5)Center for Neuroscience Services and Research, Universiti Sains Malaysia, Health Campus, Kerian Kelantan, Malaysia.<br />
Several histone deacetylase inhibitors (HDACis) are known to increase Survival Motor Neuron 2 (SMN2) expression for the therapy of spinal muscular atrophy (SMA). We aimed to compare the effects of suberoylanilide hydroxamic acid (SAHA) and Dacinostat, a novel HDACi, on SMN2 expression and to elucidate their acetylation effects on the methylation of the SMN2. Cell-based assays using type I and type II SMA fibroblasts examined changes in transcript expressions, methylation levels and protein expressions. In silico methods analyzed the intermolecular interactions between each compound and HDAC2/HDAC7. SMN2 mRNA transcript levels and SMN protein levels showed notable increases in both cell types, except for Dacinostat exposure on type II cells. However, combined compound exposures showed less pronounced increase in SMN2 transcript and SMN protein level. Acetylation effects of SAHA and Dacinostat promoted demethylation of the SMN2 promoter. The in silico analyses revealed identical binding sites for both compounds in HDACs, which could explain the limited effects of the combined exposure. With the exception on the effect of Dacinostat in Type II cells, we have shown that SAHA and Dacinostat increased SMN2 transcript and protein levels and promoted demethylation of the SMN2 gene.<br />
2. Arch Pharm Res. 2015 Oct 19. [Epub ahead of print]<br />
Strategy for enhancing the therapeutic efficacy of histone deacetylase inhibitor dacinostat: the novel paradigm to tackle monotonous cancer chemoresistance.<br />
Ganai SA(1).<br />
Author information:<br />
(1)Plant Virology and Molecular Pathology Laboratory, Division of Plant Pathology, Sher-e-Kashmir University of Agricultural Sciences and Technology of Kashmir, Shalimar, Srinagar, 190025, India. [email protected].<br />
Histone deacetylases (HDACs) regulate gene expression by creating the closed state of chromatin via histone hypoacetylation. Histone acetylation deregulation caused by aberrant expression of classical HDACs leads to imprecise gene regulation culminating in various diseases including cancer. Histone deacetylase inhibitors (HDACi), the small-molecules modulating the biological function of HDACs have shown promising results in inducing cell cycle arrest, differentiation and apoptosis in tumour models. HDACi do not show desired cytotoxic effect when used in monotherapy due to triggering of various resistance mechanisms in cancer cells emphasizing the desperate need of novel strategies that can be used to overcome such challenges. The present article provides intricate details about the novel HDACi dacinostat (LAQ-824) against multiple myeloma and acute myeloid leukaemia. The distinct molecular mechanisms modulated by dacinostat in exerting cytotoxic effect against the defined malignancies have also been detailed. The article also explains the strategy that can be used to circumvent the conventional therapy resistant cases and for enhancing the therapeutic efficacy of dacinostat for effective anticancer therapy.<br />
3. J Med Chem. 2010 Apr 8;53(7):2952-63. doi: 10.1021/jm100007m.<br />
Conformational refinement of hydroxamate-based histone deacetylase inhibitors and exploration of 3-piperidin-3-ylindole analogues of dacinostat (LAQ824).<br />
Cho YS(1), Whitehead L, Li J, Chen CH, Jiang L, Vögtle M, Francotte E, Richert P, Wagner T, Traebert M, Lu Q, Cao X, Dumotier B, Fejzo J, Rajan S, Wang P, Yan-Neale Y, Shao W, Atadja P, Shultz M.<br />
Author information:<br />
(1)Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.<br />
Inspired by natural product HDAC inhibitors, we prepared a series of conformationally restrained HDAC inhibitors based on the hydroxamic acid dacinostat (LAQ824, 7). Several scaffolds with improved biochemical and cellular potency, as well as attenuated hERG inhibition, were identified, suggesting that the introduction of molecular rigidity is a viable strategy to enhance HDAC binding and mitigate hERG liability. Further SAR studies around a 3-piperidin-3-ylindole moiety resulted in the discovery of compound 30, for which a unique conformation was speculated to contribute to overcoming increased lipophilicity and attenuating hERG binding. Separation of racemate 30 afforded 32, the R enantiomer, which demonstrated improved potency in both enzyme and cellular assays compared to dacinostat.<br />
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