Epigenetics and DNA methylation in cancer

Table 5 Epigenetic drug discovery challenges

Category	Issues
Target selection	Few activating mutations, translocations or syntethic lethal relationships known limited high-quality antibodies to epigenetic proteins and histone marks (e.g., confirm target expression linkage of target to mark) Biology driving cancer phenotype unknown or poorly understood Post-translation modification of histone vs non-histone substrates by "epigenetic" targets unclear
Chemistry	Existing chemical librairies may not have adeguate diversity to provide goog strating points Few crystal structures solved; are structrues relevant if not reflecting complete complex?
Assay development	Few reference compunds to establish assy signal window, sensitivity, reproducibility Are binding or enzyme configured to properly reflect physiological context? Production of actibe enzymes is difficult, may require multimeric complex and specific sunstrate (nucleosome, histone, non-histone) Limited high-quality antibodies to epigenetic proteins and histone marks (quantify mark or target gene product)
In vivo biology	Histone marks and target genes slow to change, require longer-duration studies to assess engagement (PD biomarker) May necessitate higer compund requirement to conduct studies, earlier optimation of PK properties than traditional paradigm May require novel models for tumors with mutation or traslocations
Toxicology	Acute and/or chronic liabilities of specific isofrom targed epigenetic therapies currently unknown Knockout animal data limited; inducibile knockouts, dominant negatives preferred but more scarce and technically challening
Clinical	Identify and implement appropriate patient selection markers, more challenging if not activating mutation (overexpression, gene profile?) Identify and implement suitable PD marker (posttranslational modification or mark, target gene, surrogate tissue or tumor?) Epigenetic changes at metastatic sites can differ from primary tumor, which should be targed clinically?

Adapted by Campbell et al[44], 2014.