RALGEF inhibitors suppress RAS-driven pancreatic cancer and metastasis

RAS oncoproteins are the most frequently activated oncoproteins in cancer. Development of direct RAS inhibitors has proved technically challenging and has had limited success in the clinic. Those RAS inhibitors that have been approved tend to suffer from resistance development. Consequently, many attempts have focused on inhibiting RAS indirectly by targeting its immediate downstream effectors. RAS binds and activates three main effector classes to drive transformation: RAF kinases, phosphoinositide 3 (PI-3) kinase and Ras-like (RAL) small GTPases (RALGEF) exchange factors. Multiple FDA-approved inhibitors for RAF and PI-3 kinase exist. So far, they have proved to be of limited effectiveness in patients. However, no inhibitors of the RALGEF effectors with demonstrated antitumor activity have been reported. This is despite the considerable body of evidence supporting a critical role for the RALGEF/RAL pathway in facilitating the in vivo transforming effects of activated RAS. Here, we describe the first small molecule pan-RALGEF inhibitor. We show the inhibitor specifically suppresses RAS/RAL signaling and exhibits antitumor effects in xenograft experiments, including a patient-derived xenograft (pdx) model. This first-in-class compound may lead to the development of more effective therapies for a broad range of RAS-driven tumors.