The drug discovery division of IkerChem is focused on the area of cancer epigenetics.
Simply, this refers to heritable changes in gene expression that occur without alteration in DNA sequence.
There are two main, but interconnected, epigenetic modes of action: DNA methylation and modification of histones.
The main targets of our research therefore are:
The main targets of our research therefore are:
- Histone Deacetylase Inhibitors (HDAC) Histone N-terminal tails are crucial in helping to maintain chromatin stability and are subject to numerous modifications such as acetylation; histone acetylation tends to open up chromatin structures therefore histone acetyl transferases (HATs) generally are transcriptional activators whereas histone deacetylases (HDACs) tend to be repressors. HDACs are an important target in cancer epigenetics and IkerChem is making excellent progress in the design and development of potent pan and isoform specific HDAC inhibitors.
- DNA Methyltransferase Inhibitors (DNMT) DNA methylation was the first epigenetic alteration to be observed in cancer cells. Hypermethylation of CpG islands at tumour suppressor genes causes these to switch off whereas global hypomethylation leads to genome instability and inappropriate activation of oncogenes. It seems that genomic DNA methylation levels, which are maintained by DNA methyltransferase (DNMT) enzymes, are delicately balanced within cells; overexpression of DNMTs is linked to cancer in humans and their deletion in animals is lethal. Therefore inhibition of DNMTs is an important target and IkerChem has designed a series of families of non-covalent inhibitors which are demonstrating excellent potential as treatment for cancer.
- SIRT Modulators Applications are known to exist in Neurodegenerative diseases within the HDAC and SIRT target areas and we are exploring these possibilities with our molecules; the SIRT inhibitors we have designed are also interesting in the oncology field.
- JMJ2DC(GASC1) Inhibitors (JMJ) Histone lysine methylation forms part of the epigenetic modifications and has an important role in regulating chromatin dynamics and transcription. Recently, three distinct classes of enzymes that directly remove methyl marks from histones have been identified, Jumonji-domain-containing (JmJC) family of proteins being one of these.
- Nano There is scientific evidence that points out the synergies existing between HDAC inhibition and DNMT inhibition. For this reason, Ikerchem has developed both type of inhibitors as two different families of molecules. In addition, we are also designing a novel family of small molecular weight compounds that join together the pharmacophores of our best HDAC inhibitors and our most promising DNMT inhibitors, in an attempt to inhibit both enzymes with a single and potent drug.
Unlike acetylation, which generally correlates with transcriptional activation, histone lysine methylation can signal either activation or repression depending on the particular lysine residue that is methylated. In addition, methylated lysines can be in a mono-, di-, or tri-methylated form, and these different forms differentially affect chromatin structure and are responsible for transcriptional activation as well as silencing. However, some of the more stable marks, in particular H3K9me3 and H3K36me3 are specific staining profiles in interphase chromatin that can be correlated with diverse cell fates or with different proliferative potentials, which would be of therapeutic significance.
