The Mitogen-Activated Protein Kinase (MAPK) pathway is one of the most frequently mutated oncogenic signaling pathways in human cancer, and members of this pathway, including MEK, have long been pursued as drug targets. To date, the use of MEK inhibitors has been limited by toxicities and the rapid development of resistance. Arvin Dar, a molecular oncologist from the Icahn School of Medicine at Mount Sinai, is studying the molecular structure and function of MEK to design safer and more effective therapies. In previous research, his lab solved the high-resolution X-ray co-crystal structures of MEK bound to the scaffold protein KSR and the MEK inhibitor trametinib, a drug approved for use in melanoma and non-small cell lung cancer. Analysis of those crystal structures revealed an unusual mode of binding called “interfacial binding.” Dar observed that MEK formed a complex with KSR and that the two together bound to trametinib at their interface. Dar hypothesized that this unusual binding arrangement could be the source of some of the unique pharmacological properties of trametinib relative to other MEK inhibitors. To test this idea, he created a tool compound called “trametiglue”, which has enhanced interfacial binding properties and shows promise in overcoming drug resistance. In this project, Dar is further evaluating the properties of trametiglue and its analogs to develop them as in vivo chemical probes as well as potential leads for new therapeutics. He is also exploring a broader application of molecular glues to regulatory complexes in the RAS pathway. This work could lead to the next generation of drugs to treat RAS-MAPK driven cancers.
Brady DC, Hmeljak J, Dar AC. Understanding and drugging RAS: 40 years to break the tip of the iceberg. Dis Model Mech. 2022.
Chow A, Khan ZM, Marsiglia WM, Dar AC. Conformational control and regulation of the pseudokinase KSR via small molecule binding interactions. Methods Enzymol. 2022.