Future Prospects for Pharmacogenetics in the Quest for Personalized Medicine.

Future prospects for pharmacogenetics in the quest for personalized medicine.

J Psychosoc Nurs Ment Health Serv. 2012 Dec; 50(12): 13-6
Howland RH

Understanding pharmacogenetic differences in drug response and tolerability has been an important area of research in personalized medicine, but the clinical utility of pharmacogenetics testing has not been established. Identification of genetic polymorphisms due to single nucleotide polymorphisms is the most common approach, but this does not take into account the potential relevance of copy number variants, noncoding RNA gene regulation, gene-gene and gene-interactions, and epigenetic modifications, which increase the complexity of pharmacogenomics research. HubMed – drug


Energy based pharmacophore mapping of HDAC inhibitors against class I HDAC enzymes.

Biochim Biophys Acta. 2013 Jan; 1834(1): 317-28
Kalyaanamoorthy S, Chen YP

Histone deacetylases (HDACs) are important class of enzymes that deacetylate the ?-amino group of the lysine residues in the histone tails to form a closed chromatin configuration resulting in the regulation of gene expression. Inhibition of these HDACs enzymes have been identified as one of the promising approaches for cancer treatment. The type-specific inhibition of class I HDAC enzymes is known to elicit improved therapeutic effects and thus, the search for promising type-specific HDAC inhibitors compunds remains an ongoing research interest in cancer drug discovery. Several different strategies are eployed to identify the features that could identify the isoform specificity factors in these HDAC enzymes. This study combines the insilico docking and energy-optomized pharmacophore (e-pharmacophore) mapping of several known HDACi’s to identify the structural variants that are significant for the interactions against each of the four class I HDAC enzymes. Our hybrid approach shows that all the inhibitors with at least one aromatic ring in their linker regions hold higher affinities against target enzymes, while those without any aromatic rings remain as poor binders. We hypothesize the e-pharmacophore models for the HDACi’s against all the four Class I HDAC enzymes which are not reported elsewhere. The results from this work will be useful in the rational design and virtual screening of more isoform specific HDACi’s against the class I HDAC family of proteins. HubMed – drug


Developing novel C-4 analogues of pyrrole-based antitubulin agents: weak but critical hydrogen bonding in the colchicine site.

Medchemcomm. 2013; 4(2): 417-421
Da C, Telang N, Hall K, Kluball E, Barelli P, Finzel K, Jia X, Gupton JT, Mooberry SL, Kellog GE

The synthesis, biological evaluation and molecular modeling of a series of pyrrole compounds related to 3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid that evaluates and optimizes C-4 substituents are reported. The key factor for microtubule depolymerization activity appears to be the presence of an appropriately positioned acceptor for Cys241? in the otherwise hydrophobic subpocket A. HubMed – drug


Bioactivity-Guided Identification and Cell Signaling Technology to Delineate the Lactate Dehydrogenase A Inhibition Effects of Spatholobus suberectus on Breast Cancer.

PLoS One. 2013; 8(2): e56631
Wang Z, Wang D, Han S, Wang N, Mo F, Loo TY, Shen J, Huang H, Chen J

Aerobic glycolysis is an important feature of cancer cells. In recent years, lactate dehydrogenase A (LDH-A) is emerging as a novel therapeutic target for cancer treatment. Seeking LDH-A inhibitors from natural resources has been paid much attention for drug discovery. (SS) is a common herbal medicine used in China for treating blood-stasis related diseases such as cancer. This study aims to explore the potential medicinal application of SS for LDH-A inhibition on breast cancer and to determine its bioactive compounds. We found that SS manifested apoptosis-inducing, cell cycle arresting and anti-LDH-A activities in both estrogen-dependent human MCF-7 cells and estrogen-independent MDA-MB-231 cell. Oral herbal extracts (1 g/kg/d) administration attenuated tumor growth and LDH-A expression in both breast cancer xenografts. Bioactivity-guided fractionation finally identified epigallocatechin as a key compound in SS inhibiting LDH-A activity. Further studies revealed that LDH-A plays a critical role in mediating the apoptosis-induction effects of epigallocatechin. The inhibited LDH-A activities by epigallocatechin is attributed to disassociation of Hsp90 from HIF-1? and subsequent accelerated HIF-1? proteasome degradation. study also demonstrated that epigallocatechin could significantly inhibit breast cancer growth, HIF-1?/LDH-A expression and trigger apoptosis without bringing toxic effects. The preclinical study thus suggests that the potential medicinal application of SS for inhibiting cancer LDH-A activity and the possibility to consider epigallocatechin as a lead compound to develop LDH-A inhibitors. Future studies of SS for chemoprevention or chemosensitization against breast cancer are thus warranted. HubMed – drug