Huda Zahid receives IEM Doctoral Fellowship

Huda Zahid, a fourth-year graduate student working with Professor William Pomerantz, has received a 2020-2021 Engineering in Medicine Doctoral Fellowship from the University of Minnesota Institute for Engineering in Medicine.

Huda is interested in "Multidisciplinary Training in Cancer Therapeutics: Developing Small-Molecule Inhibitors of the Epigenetic Protein BPTF using Virtual Screening."

Bromodomains are protein-protein interaction modules involved in epigenetic regulation of gene expression, typically through the recognition of acetylated lysine residues in histones. Bromodomain-containing proteins are involved in several diseases, including cancer, inflammation, and viral replication. While numerous small molecule probes have been developed for the well-studied BET (bromodomain and extra terminal) family, few have been reported for the 53 non-BET bromodomains. Potent and selective chemical probes are, therefore, required to enhance our biological understanding of the non-BET bromodomain family.

Among them, BPTF is known to play an important role in chromatin remodeling and has been identified as a target for anticancer therapy. This study aims to develop potent small-molecule probes for the BPTF bromodomain that demonstrate selectivity over BET and other non-BET bromodomains such as BRD4, BRDT, PCAF, and GCN5. This involves structure-based design and synthesis of analogues of the pyridazinone scaffold previously reported for another set of bromodomains (PCAF/GCN5). Biophysical assays, including Protein-Observed Fluorine (PrOF) NMR and AlphaScreen, are used to study the in vitro interaction of small-molecule inhibitors with the bromodomain of BPTF and to quantify their binding affinity. Several cocrystal structures of the synthesized compounds are also obtained with BPTF, providing insight into key interactions with the protein and guiding future medicinal chemistry efforts.