Department of Chemistry, Graduate School of Science
Having earned my BSc in Pharmaceutical Sciences from Utrecht University and an MSc in Medicinal (Organic) Chemistry from Vrije Universiteit Amsterdam, I have established a robust foundation in life sciences and their manipulation. Currently, my research revolves around discovering ligands/probes for KDM4C by exploiting the kinetics of target-ligand association and dissociation. The objective is to achieve isoform selectivity towards KDM4C over other closely related KDM4 sub-members by virtue of binding kinetics. I am employing three distinct strategies:
DNA-Encoded Macrocyclic Peptide Library Screening: Using DNA-encoded chemical libraries (DECLs), I construct extensive macrocyclic peptide libraries to identify potent KDM4C ligands. DECLs provide an ultrahigh-throughput platform, incorporating diverse structural elements such as N-methylated, D-, and non-canonical amino acids. These libraries offer structurally diverse ligands with potential improvements in pharmacodynamic and pharmacokinetic properties, including oral bioavailability, cell permeability, and metabolic stability. Additionally, DECL hits often already exhibit slow association/dissociation kinetics due to the experimental setup's inherent nature of the affinity screening.
Small-Molecule Inhibitors: Utilizing computer-aided drug design and rational design, my objective is to identify small-molecule inhibitors that target regions of KDM4C situated distantly from the catalytic pocket, in addition to leveraging well-established binding interactions documented in the literature. These specific regions display increased sequence variation among KDM4 isoforms. Furthermore, through the exploration of sp3-rich, chiral cyclic scaffolds, isoform-selectivity might be achieved, as indicated by observations in docking studies.
Covalent Inhibitors: Acknowledging the crucial role of Lys241 in KDM4A for enzyme activity, a role entirely nullified by mutation to alanine/leucine, a parallel significance is hypothesized for Lys243 in KDM4C. Targeting this specific lysine residue in KDM4C covalently is a strategic approach to fully suppress its activity. In pursuit of this goal, a series of reversible covalent boron-based compounds will be synthesized and tested.