The MEK-RAF molecular glue IK-595 has potent antitumor activity across RAS/MAPK pathway-altered cancers.

MAPK pathway alterations are the most common oncogenic drivers. Among the approved therapies targeting this pathway are RAS, MEK and RAF inhibitors. However, therapeutic resistance and toxicities have limited their clinical success. Here, to overcome these liabilities, we developed IK-595, a potent MEK-RAF molecular glue. IK-595 traps MEK in an inactive complex with all RAF isoforms. In addition, IK-595 precludes CRAF-mediated MEK reactivation and ARAF heterodimerization, allowing for prolonged target engagement and durable MAPK pathway inhibition. This translates into superior antitumor activity across a wide range of cancer model indications harboring MAPK pathway alterations. A key advantage of IK-595 is its ability to achieve transient high plasma exposure affording a larger therapeutic window. The unique mechanism of action and improved tolerability positions IK-595 as an ideal combination partner. IK-595 is an MEK-RAF molecular glue that prolongs pathway inhibition while providing a broader therapeutic window as monotherapy and in combination.