Atropisomerism is a form of chirality that arises from hindered rotation about a sp2-sp2 bond. Over 85% of FDA approved kinase inhibitors possess a rapidly interconverting atropisomeric axis, highlighting the significance of this phenomenon in drug discovery. Building off of this concept, we hypothesized that the low energy conformational window about the chiral axis is a key factor for potency and selectivity. We subsequently realized that selectivity can be improved by preorganizing the chiral axis in a conformational window that corresponds to the desired target. We are currently employing this hypothesis to obtain a potent, and selective inhibitor of the receptor tyrosine kinases (RTKs) KIT and PDGFRA. Activating mutations and genetic alterations in these kinases have been identified in many cancers, including gastrointestinal stromal tumors, gliomas, and lung cancers. Our conformational mapping of the pyridone kinase inhibitor scaffold revealed that the FDA approved KIT/PDGFRA inhibitor, Ripretinib, binds KIT in an orthogonal conformation about the aryl-heterocycle axis. While Ripretinib is somewhat selective because it has been found to target a broad range oncogenic and drug resistant KIT/PDGFRA variants, it has also been shown to inhibit several other RTKs, resulting in adverse side effects seen in patients. Thus, we hypothesized that Ripretinib’s selectivity can be improved to target KIT/PDGFRA through tuning its dihedral angle in a near-orthogonal conformation, aligning with the preferred low energy conformational binding window of these kinases. We plan to achieve this through incorporating steric bulk adjacent to the chiral axis in the Ripretinib scaffold to stabilize its dihedral angle in an orthogonal conformation. In order to validate our hypothesis, we will obtain IC50 values, and evaluate our inhibitors in cellular models of KIT/PDGFRA driven cancers to study the effect of our inhibitors in vitro.

Leveraging conformational control to obtain selective kinase inhibitors

ACS Spring 2022

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