Second-Generation JK-206 Targets the Oncogenic Signal Mediator RHOA in Gastric Cancer

SIMPLE SUMMARY: Ras homologous A (RHOA), a signal mediator and a GTPase, is associated with the progression of gastric cancer (GC). We present novel RHOA inhibitors designed for greater anti-GC potency by means of lead optimization. The RHOA → BIRC5 signaling circuit was found to be a new therapeutic strategy for regulating GC proliferation and migration. ABSTRACT: Ras homologous A (RHOA), a signal mediator and a GTPase, is known to be associated with the progression of gastric cancer (GC), which is the fourth most common cause of death in the world. Previously, we designed pharmacologically optimized inhibitors against RHOA, including JK-136 and JK-139. Based on this previous work, we performed lead optimization and designed novel RHOA inhibitors for greater anti-GC potency. Two of these compounds, JK-206 and JK-312, could successfully inhibit the viability and migration of GC cell lines. Furthermore, using transcriptomic analysis of GC cells treated with JK-206, we revealed that the inhibition of RHOA might be associated with the inhibition of the mitogenic pathway. Therefore, JK-206 treatment for RHOA inhibition may be a new therapeutic strategy for regulating GC proliferation and migration.