There’s an abundant number of kinase proteins in the human genome and their aberrant activity can lead to life threating disease including cancer. Consequently, a vast amount of medicinal research has been focused on the synthesis of small molecule kinase inhibitors. Due to the commonality of the syntheses of these molecules, 83% of FDA approved kinase inhibitors exhibit an extended form of chirality known as atropisomerism. Although these inhibitors are considered achiral, they bind the protein’s active site in a conformationally specific fashion. Meaning that one conformation acts towards the desired activity, while the others might bind off-target and lead to side-effects in patients.<br/><br/>Research has demonstrated that we can successfully exploit atropisomerism to access certain dihedral angle confirmations to increase selectivity and potency towards RET kinase. After several iterations of optimization, we obtained an inhibitor with nanomolar IC50 towards RET. An analysis of bound ligand’s dihedral angles, we noticed that mutant EGFR kinases bound their ligands in a similar dihedral angle range as RET. We hypothesized that our lead inhibitor would have secondary activity towards EGFR mutants. This was validated, finding it had low micromolar activity towards cell line containing EGFR mutations.<br/><br/>Going forward our goal is to synthesize inhibitors selective for EGFR mutants, an emerging target for resistant lung cancers. In silico docking studies showed a unique shape of mutant EGFR’s hydrophobic pocket. We will prioritize the synthesis of inhibitors that will target this region by diversifying the top aryl rings of our kinase inhibitors. To fully exploit the hydrophobicity of EGFR binding pocket, we are looking to synthesize atropisomerically stable versions of tilted aromatic di-aryl PPY inhibitors, as well as indole derivatives. Additionally, we aim to synthesize type II inhibitors that target specifically in-active conformations, to potentially lower the inhibitor’s off-rate when bound to EGFR.

Leveraging atropisomerism to obtain a selective inhibitor for EGFR mutants

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.