Development of ATP-competitive inhibitors of KSR for the treatment of cancer

DESCRIPTION (provided by applicant): The lack of effective treatments for mutant RAS driven cancers remains a critical unmet need in modern cancer therapy. Several lines of recent evidence suggest that Kinase Suppressor of RAS (KSR) is a viable target forsmall molecule therapeutics. It has been established that KSR binds constitutively to MEK and transiently to RAF and Erk during active RAS signaling, and these binding events are all mediated at least in part through KSR's protein kinase domain. Recent structural studies by Wellspring's scientific co-founder, Kevan Shokat suggest that KSR's kinase domain functions as a bifunctional dynamic scaffold, bringing together key proteins for RAS signaling (MEK and RAF) and allosterically modulating RAF mediated MEKphosphorylation. A generic kinase inhibitor with the ability to modulate the allosteric switch in KSR was recently reported by Shokat and coworkers, suggesting a possible starting point to develop novel drugs that function as chemical suppressors of