STUDIES TOWARDS THE DEVELOPMENT OF HIGHLY SELECTIVE EPIGENETIC SMALL MOLECULE PROBES FOR THE ALKB FAMILY OF NUCLIEIC ACID DEMETHYLASES

Abstract

The AlkB family, namely ALKBH1-8 and FTO in humans, catalyse demethylation of nucleic acid or histones to play critical roles in gene expression. They are 2-oxoglutarate and Fe (II) dependent dioxygenases with highly conserved structural features which makes their subfamily-selective inhibition challenging. However, their medical importance necessitates the development of selective probes to understand their functional and molecular mechanisms better. This thesis involves studying two different approaches to design subfamily-selective probes targeting the AlkB enzymes. In the first approach, we used multiple AlkB proteins as structural templates to guide the self-assembly of selective ligands. This multiprotein dynamic combinatorial chemistry approach led to the discovery of subfamily-selective probes against FTO and ALKBH3. In the second approach, we used the structural understanding of ALKBH1 to guide the design of selective probes. Our designed molecules showed at least ~10 folds selectivity for ALKBH1 probably by interacting with the unique Flip2 residues in ALKBH1.