Organic Seminar - Arvin Dar

Dar laboratory research is focused on understanding the structure and mechanism of protein complexes in cancer pathways through the development of tool compounds and therapeutic leads. One such area focuses on the development of molecular glues that operate at the interface of RAS effector complexes including RAF, MEK, and the pseudokinase scaffold KSR. Previously, several inhibitors targeting these components were thought to bind in pockets composed of the individual polypeptides. I will present structural and in vivo binding data demonstrating how molecular glue interactions on wild-type and mutant MAPK complexes impact pathway inhibition and adaptive feedback mediated by rebound signaling. I will also present structure-based approaches for developing next generation inhibitors and molecular glues with the goal of improving target engagement and combinatorial activity to mitigate the emergence of drug resistance. Finally, how these findings may apply to a larger class of kinases and drug targets that operate as scaffolds for functionally related enzymes and disease drivers will be discussed.