Revere Pharmaceuticals is developing novel small molecule therapeutics that inhibit Rac1 signaling, a key but unexploited cancer target. Rac1 is a critical signaling protein that promotes cancer cell growth, migration, invasion, and tumor angiogenesis—all essential hallmarks of metastatic disease progression.
Overexpression and activation of Rac1 correlates with inferior prognosis in multiple cancer types including ovarian, lung, breast, colorectal, and gastric cancer and is commonly associated with resistance to chemotherapy and other targeted cancer therapeutics.
Rac1 is a member of a protein family known as Rho small GTPases. Rac1 cycles between an inactive form (bound to GDP) and an active form (bound to GTP). Activation is mediated by guanine nucleotide exchange factors (GEFs) which promote the exchange of GDP by GTP. GTPase activating proteins (GAPs) inactivate Rac1 signaling by inducing GTP hydrolysis (see figure above). Revere’s REV-440 mechanism of action stabilizes inactive GDP bound Rac1, thereby inhibiting Rac1’s ‘downstream’ cancer promoting consequences.