VVD 065

VVD 065 is an orally active KEAP1 -dependent NRF2 molecular glue degrader with a KEAP1 K D of 65 nM. VVD 065 covalently engages KEAP1 at Cys151, allosterically stabilizes KEAP1 - CUL3 complex formation and enhances NRF2 polyubiquitination and proteasomal degradation. VVD 065 can be used for the research of esophageal squamous cell carcinoma, lung cancer, head-and-neck cancer, uterine cancers ^{[1] [2] [3]}.

In Vivo, VVD-065 (0.3-50 mg/kg; p.o.; QD or BID) induces robust NRF2 degradation and tumor growth inhibition in KYSE70 xenograft mice^[3]. VVD-065 (2-50 mg/kg; p.o.; QD or BID) produces potent, sustained tumor growth inhibition in HCC95 xenograft mice^[3]. VVD-065 (50 mg/kg; p.o.; QD or BID) drives tumor growth inhibition in diverse PDX models^[3]. VVD-065 (50 mg/kg; p.o.; QD) improves overall survival and reduces tumor burden in orthotopic KLN-205 syngeneic mice^[3].

In Vitro, VVD 065 potently reduces NRF2 protein levels in wild-type KEAP1/NRF2, KEAP1-mutant, and NRF2-mutant cellular settings, inhibits NRF2-dependent gene expression, and suppresses proliferation of NRF2-dependent cancer cell lines at low nM concentrations^[2].

References:
[1]. Adamopoulos C, et al. Turning KEAP1 against NRF2. Nat Chem Biol. 2026 May;22(5):680-682.
[2]. Roy N, et al. Abstract PR011: Discovery of VVD-065, a first-in class allosteric molecular glue of the Keap1-Cul3 E3-ligase complex for the treatment of NRF2 activated cancers. Mol Cncer Ther. 2023 Dec 01;22:PR011.
[3]. Roy N, et al. A Covalent Allosteric Molecular Glue Suppresses NRF2-Dependent Cancer Growth. Cancer Discov. 2026 May 1;16(5):953-975.