Revere Pharmaceuticals | Rac1 GTPase

Understanding the role of Rac1

Rac1 GTPase and its variants are proteins that function as central signaling nodes for diverse pathways that drive various cancer promoting processes including cell growth, migration, invasion, and angiogenesis. These proteins switch between the inactive guanosine diphosphate (or GDP-bound form) and the active guanosine triphosphate (or GTP-bound form) which recruits other downstream effector proteins to activate oncogenic pathways.

While GTPases have been elusive to targeted drug discovery, we have developed proprietary methods to target these signaling proteins, including high throughput screening methods. Currently, Revere is focused on Rac1 and its variants and Cdc42, a closely related Rho GTPase.

Rac1: a critical but unexploited cancer target

Aberrant Rac1 signaling promotes cancer cell growth, migration, invasion, and tumor angiogenesis. Overexpression and activation of Rac1 correlate with inferior prognosis in multiple cancers and are associated with resistance to chemotherapy and other therapeutics.

Revere’s drug discovery efforts address cancers with overexpressed wild type Rac1, the Rac1b oncogenic splice variant, and the Rac1 P29S mutant to address cancers characterized by these aberrations. Companion diagnostics for the Rac1b and P29S programs will enable precision oncology patient selection strategies.

Xenograft data reveals excellent in vivo single agent activity of Revere compound 32661. The combination of our compound with a standard-of-care HER2 targeted agent shows prolonged tumor growth inhibition with no toxicity.

Our novel Rac1 inhibitors show significant anti-tumor activity as single agents and in combination with standards of care in animal models of breast, prostate, kidney, melanoma, ovarian, and colorectal cancers.

Rac1 GTPase activation and signaling in cancer

Cdc42: an emerging Rho GTPase target for cancer and viral diseases

Cdc42, a Rho GTPase closely related to Rac1, is linked to multiple cancers, including cervical, stomach, esophagus, prostate, and lung cancers. In addition to being implicated in metastatic disease progression, it has important immune modulating actions, including promoting immunosuppressive regulatory T-cell activity which inhibits cancer-killing CD8+ T-cells. Recent research supports an important role for Cdc42 and its downstream effectors in coronavirus infections.

Cdc42 is not commonly mutated in cancer but is overexpressed or hyperactivated. With our GTPase discovery platform, Revere is developing selective Cdc42 inhibitors to treat cancer and exploring applications for treatment of COVID-19.

Targeting Rac1 GTPases: “molecular switches” that drive cancer progression

Understanding the role of Rac1

Rac1: a critical but unexploited cancer target

Rac1 GTPase activation and signaling in cancer

Cdc42: an emerging Rho GTPase target for cancer and viral diseases

Learn More