Targeting epigenetic modifiers:
Inhibitors of histone methyltransferases
Reversible histone methylation is an emerging new target in the field of epigenetic regulation. Here, we review histone methyltransferases in light of their role in disease formation and with regard to the state of the art in drug discovery.
DNA methyltransferases inhibitors
This review describes current knowledge concerning DNA methyltransferases (DNMT) biology and the two main classes of DNMT inhibtors.
Epigenetics—an emerging and highly promising source of new
Epigenetic modifications to DNA and its associated histone proteins are major influences on gene expression. This regulatory process is disrupted in cancer and a range of chronic human diseases, and provides attractive new intervention points and targets for drug discovery.
Development of second generation epigenetic agents
This review focuses on the progress in the development of the second generation of epigenetic modifiers able to modulate histone marks, and restore normal gene transcription.
Inhibition of bromodomain-mediated
protein– protein interactions as a novel therapeutic strategy
Small molecule inhibitors of acetyl lysine–bromodomain interactions emerge as novel epigenetic tools with potential for therapeutic approaches.
Polyamine-based small molecule epigenetic modulators
Multiple series of HDAC and LSD1 inhibitors have been developed that increase histone lysine methylation and promote the re-expression of aberrantly silenced genes that are important in human cancer..
carboxylic acids as novel
inhibitors of histone acetyltransferases
Virtual screening has identified rhodanine containing carboxylic acids as new inhibitors of histone acetyltransferases.
Developing novel non-hydroxamate
histone deacetylase inhibitors: the chelidamic warhead
The dimethyl 4-hydroxypyridine-2,6-dicarboxylate is a valuable scaffold for HDAC inhibitor design as a replacement of the well-known hydroxamate function.
Binding free energy calculations and biological testing of novel thiobarbiturates as
inhibitors of the human NAD+ dependent histone deacetylase Sirt2
Novel thiobarbiturates were identified by virtual screening and MM-PBSA calculation as potent sirtuin inhibitors which represent useful probes for cellular studies.
hydroxylation of the splicing factor lysyl hydroxylase, JMJD6
The lysyl hydroxylase, JMJD6 undergoes self-hydroxylation resulting in the 5S-hydroxylysine product.
Click JAHAs: conformationally restricted
ferrocene-based histone deacetylase inhibitors
The ferrocene analogue 4b had an IC50 = 4 nM (HDAC1), 180 nM (HDAC8) and was effective in a Xenopus model of tubulin deacetylation. Analogue 4a displayed mainly μM IC50 values against HDACs apart from HDAC6 (IC50 = 69 nM).
Structure–activity relationships of
methyl-lysine reader antagonists
The structure–activity relationships for small molecule antagonists of the Malignant Brain Tumor (MBT) domain family of methyl-lysine readers are described and activity demonstrated in histone peptide pull-down assays.
About this collection
MedChemComm is delighted to publish this collection of articles in the emerging field of epigenetics research, guest edited by Dr Mark Bunnage (Pfizer) and Professor Rasmus Prætorius Clausen (University of Copenhagen).
Read their introduction to the issue on the MedChemComm blog.