Discovery of first novel sigma/HDACi dual-ligands with a potent in vitro antiproliferative activity.

Designing and discovering compounds for dual-target inhibitors is challenging to synthesize new, safer, and more efficient drugs than single-target drugs, especially to treat multifactorial diseases such as cancer. The simultaneous regulation of multiple targets might represent an alternative synthetic approach to optimize patient compliance and tolerance, minimizing the risk of target-based drug resistance due to the modulation of a few targets. To this end, we conceived for the first time the design and synthesis of dual-ligands σR/HDACi to evaluate possible employment as innovative candidates to address this complex disease. Among all synthesized compounds screened for several tumoral cell lines, compound 6 (Kiσ1R = 38 ± 3.7; Kiσ2R = 2917 ± 769 and HDACs IC50 = 0.59 µM) is the most promising candidate as an antiproliferative agent with an IC50 of 0.9 µM on the HCT116 cell line and no significant toxicity to normal cells. Studies of molecular docking, which confirmed the affinity over σ1R and a pan-HDACs inhibitory behavior, support a possible balanced affinity and activity between both targets.

Cracking a cancer code histone deacetylation in epigenetic: the implication from molecular dynamics simulations on efficacy assessment of histone deacetylase inhibitors.

Epigenetic changes, histone acetylation and deacetylation in chromatin have been intensively studied due to their significance in regulating the gene expression. According to the type of tumor, the levels of histone deacetylases (HDAC) are varied. HDAC inhibitors are a new promising class of compounds that inhibit the proliferation of tumor cells. In this study, the inhibitory efficacy of some HDAC inhibitors such as vorinostat, panobinostat, abexinostat, belinostat, resminostat, dacinostat and pracinostat was studied using molecular dynamics simulation. The inhibitory efficacy was estimated by computing the enzyme's stability, positional stability of the individual amino acids and interaction energies of HDLP-inhibitor complexes. It is hoped that this investigation may improve our understanding of the atomic-level description of the inhibitor binding site and how the HDAC inhibitors change the environment of the enzyme's active site. The results obtained from the root-mean-square deviation, the radius of gyration, solvent-accessible surface area, root-mean-square fluctuation, stride server and Ramachandran plot have revealed that the stability of HDLP enzyme with vorinostat, panobinostat and abexinostat is higher than the other studied complexes. According to the calculated values for MM-PBSA, LIE, semi-LIE binding free energies and interaction energies, the stability of the HDLP enzyme varies as panobinostat > abexinostat > vorinostat where resminostat complex showed relatively low stability. The ligandability and drugability values also give the same trend as above. The findings revealed that the panobinostat and abexinostat are potential lead compounds as reference inhibitor vorinostat. Therefore, it is possible to use these drugs as HDAC inhibitors in clinical practices. Also, the outcomes of this study could be utilized to identify new inhibitors for clinical research.Communicated by Ramaswamy H. Sarma.

Inhibition of class IIa histone deacetylase activity by gallic acid, sulforaphane, TMP269, and panobinostat.

Histone deacetylase (HDAC) inhibitors are gaining increasing attention as potential therapeutics for cardiovascular diseases as well as cancer. We recently reported that the class II HDAC inhibitor, MC1568, and the phytochemical, gallic acid, lowered high blood pressure in mouse models of hypertension. We hypothesized that class II HDACs may be involved in the regulation of hypertension. The aim of this study was to determine and compare the effects of well-known HDAC inhibitors (TMP269, panobinostat, and MC1568), phytochemicals (gallic acid, sulforaphane, and piceatannol), and anti-hypertensive drugs (losartan, carvedilol, and furosemide) on activities of class IIa HDACs (HDAC4, 5, 7, and 9). The selective class IIa HDAC inhibitor, TMP269, and the pan-HDAC inhibitor, panobinostat, but not MC1568, clearly inhibited class IIa HDAC activities. Among the three phytochemicals, gallic acid showed remarkable inhibition, whereas sulforaphane presented mild inhibition of class IIa HDACs. Piceatannol inhibited only HDAC7 activity. As expected, the anti-hypertensive drugs losartan, carvedilol, and furosemide did not affect the activity of any class IIa HDAC. In addition, we evaluated the inhibitory effect of several compounds on the activity of class l HDACs (HDAC1, 2, 3, and 8) and class IIb HDAC (HDAC6). MC1568 did not affect the activities of HDAC1, HDAC2, and HDAC3, but it reduced the activity of HDAC8 at concentrations of 1 and 10 µM. Gallic acid weakly inhibited HDAC1 and HDAC6 activities, but strongly inhibited HDAC8 activity with effectiveness comparable to that of trichostatin A. Inhibition of HDAC2 activity by sulforaphane was stronger than that by piceatnnaol. These results indicated that gallic acid is a powerful dietary inhibitor of HDAC8 and class IIa/b HDAC activities. Sulforaphane may also be used as a dietary inhibitor of HDAC2 and class IIa HDAC. Our findings suggest that the class II HDAC inhibitor, MC1568, does not inhibit class IIa HDAC, but inhibits HDAC8.

Observation of panobinostat alleviates early brain injury in subarachnoid hemorrhage model / 中国基层医药

Objective To observe the effect of panobinostat (LBH589) on the early brain injury (EBI) in the model of subarachnoid hemorrhage(SAH) in SD rats.Methods SD rats were randomly divided into 4 groups:sham(10 rats) and SAH(10 rats),SAH + vehicle(20 rats) and SAH + Panobinostat (20 rats).Drug or vehicle was given by lateral-ventricular stereotaxic injection 24h before the SAH model was introduced.Water contents and the neurological scores were determined at 24h post-SAH.The levels of Ac-H3K27 in frontal and lateral lobe were detected by Western blot.Results The mean neurological score of the SAH group was higher than that of the sham group(F =13.000,P =0.007).The water content of the SAH group was higher than that of the sham group (F =8.229,P =0.019).The level of Ac-H3K27 was higher in the SAH + Panobinostat group than that in the SAH +vehicle group(F =41.250,P =0.000).The mean neurological score of the SAH + Panobinostat group was lower than that of the SAH + vehicle group(F =9.560,P =0.011).The water content of the SAH + Panobinostat group was lower than that of the SAH + vehicle group (F =8.211,P =0.020).The correlation analysis indicated that the level of acetylation of H3 was negatively correlated with the neurological score (r =-0.585,P =0.046).Conclusion Panobinostat can improve the neurological behavior and alleviate early brain injury in the SAH model.

Observation of panobinostat alleviates early brain injury in subarachnoid hemorrhage model / 中国基层医药

Objective@#To observe the effect of panobinostat (LBH589) on the early brain injury (EBI) in the model of subarachnoid hemorrhage(SAH) in SD rats.@*Methods@#SD rats were randomly divided into 4 groups: sham(10 rats) and SAH(10 rats), SAH+ vehicle(20 rats) and SAH+ Panobinostat(20 rats). Drug or vehicle was given by lateral-ventricular stereotaxic injection 24h before the SAH model was introduced.Water contents and the neurological scores were determined at 24h post-SAH.The levels of Ac-H3K27 in frontal and lateral lobe were detected by Western blot.@*Results@#The mean neurological score of the SAH group was higher than that of the sham group(F=13.000, P=0.007). The water content of the SAH group was higher than that of the sham group (F=8.229, P=0.019). The level of Ac-H3K27 was higher in the SAH+ Panobinostat group than that in the SAH+ vehicle group(F=41.250, P=0.000). The mean neurological score of the SAH+ Panobinostat group was lower than that of the SAH+ vehicle group(F=9.560, P=0.011). The water content of the SAH+ Panobinostat group was lower than that of the SAH+ vehicle group(F=8.211, P=0.020). The correlation analysis indicated that the level of acetylation of H3 was negatively correlated with the neurological score(r=-0.585, P=0.046).@*Conclusion@#Panobinostat can improve the neurological behavior and alleviate early brain injury in the SAH model.