Medicinal Chemistry and Chemical Biology

Epigenetic Chemical Probes

Epigenetics is the study of heritable changes to an organism that affect gene expression.  With the discovery that histones can be extensively post-transnationally modified to alter the expression of the genes, it has been postulated that the combination of histone marks, especially lysine acetylation and methylation, constitutes an epigenetic code that is responsible for gene regulation in normal cell differentiation and in disease progression.  In order to decipher the epigenetic code, the Structural Genomics Consortium has embarked on a program to discover thirty-seven selective chemical probes that inhibit the major families of histone modifying enzymes. 

HAT: histone acetyl transferase; HDAC: histone deacetylase; HMT: histone methyl transferase; HDM: histone demethylase.

In Oxford, the focus is on bromodomains: protein recognition domains which bind acetylated lysine and histone demethylases: enzymes which remove methyl groups from the terminal amine of histone lysine residues.  The chemical probe projects begin with screening commercial and collaborator compound collections to identify hit compounds.  Through an iterative medicinal chemistry process of x-ray crystallography, medicinal chemistry compound design, organic synthesis and screening the hit compounds are optimized for potency, selectivity and cell activity.  Members of the SGC medicinal chemistry team gain expertise in structure-based drug design, in silico compound docking, structure-activity relationship analysis and modern organic synthesis.