One step closer to targeting RAS

The RAS family of small GTPases play critical roles in many types of human cancer. Activating RAS mutations are the most frequent type of oncogene mutations in human cancers, and are especially common in pancreatic, lung, and colorectal cancer. However, failure to obtain clinically useful inhibitors for RAS or any other GTPases suggests this target family is a therapeutic challenge. Consequently, significant efforts have been shifted toward targeting of downstream effectors of RAS including the Raf-MEK-ERK kinase pathway and the PI3K-AKT-mTOR kinase pathway. A third arm of RAS effector signaling, RAL (Ras-like) has not been targeted until recently and like RAS, is activated, but unlike RAS is not commonly mutated in cancer. RAL also shares a high structure similarity with RAS and other GTPase of the RAS superfamily. The two isoforms RALA and RALB are both important drivers of the proliferation, survival and metastasis of multiple human cancers. In our recent publication we reported the discovery of small molecule inhibitors of RAL.1