Epigenetic targets in cancer
Overview of epiegenetic therapies for cancer.
Chromatin remains an important therapeutic target. The activity of established and investigational epigenetic therapies in well-defined clinical contexts has provided evidence that this strategy can be effective. Given the sheer number of potential targets, a systematic approach that identifies and validates potential drug targets is needed to focus drug development and achieve the promise of this strategy.
Aberrant DNA methylation, for example, has emerged as a recurring oncogenic event.
DNA methyltransferases PDB 101
DNA methyl transferase in action
Nucleosomes PDB 101
Histone methyl transferases
Histone acetyl tranferases
HDAC inhibitors: vorinostat, romidepsin, belinostat, and panobinostat
HMT inhibitors: tazemetostat, Valemetostat, CPI-0209, CPI-1205
Lysine demethylase inhibitors: Iadademstat, CC-90011, INCB059872
Bromodomain and extraterminal (BET) inhibitors: Molibresib, Birabresib, ZEN003694, PLX51107
IDH inhibitors: Ivosidenib, Enasidenib, Vorasidenib, Olutasidenib
Isocitrate dehydrogenase is a metabolic enzyme that is mutated in some cancers such that instead of the native reaction (isocitrate to alpha keto glutarate), it catalyzes the further reduction of alpha-keto glutarate to 2-hydroxy glutarate. This causes depletion of an important co-factor (alpha-KG) for the iron-dependent enzymes that catalyze removal of methyl groups from histones or DNA. Thus, DNA stays hyper-methylated which is often associated with cancer. In addition, 2-HG has numerous cancer-activating effects, such as cellular metabolism. See this paper for more details.
- Can an acetylated lysine also be methylated?
- How many methyl groups can lysine have?
- Would you expect different number of methyl groups to have different effect on transcription?
- Simple model of chromatin is based on charge. Argue how different lysine modifications enable or prevent transcription.
- Look at the structure of largazole