VVD-065

VVD-065 is a first-in-class, orally bioavailable, covalent allosteric molecular glue that targets the Kelch-like ECH-associated protein 1 (KEAP1)-Cullin 3 (CUL3) E3-ligase complex to promote the degradation of nuclear factor erythroid 2-related factor 2 (NRF2). Developed by Vividion Therapeutics and Degron Therapeutics, VVD-065 covalently binds to the Cys151 sensor residue on KEAP1, inducing an allosteric conformational change that enhances the affinity between KEAP1 and CUL3. This action stabilizes the active E3 ligase complex, leading to robust polyubiquitination and proteasomal degradation of NRF2. In preclinical models, VVD-065 has demonstrated significant monotherapy efficacy and synergistic tumor growth inhibition when combined with chemotherapies or radiotherapy in NRF2-activated solid tumors, such as non-small cell lung cancer (NSCLC), esophageal squamous cell carcinoma (ESCC), and head and neck squamous cell carcinoma (HNSCC).

Other names

1-[(3R)-3-[3-(4-Amino-1,3,5-triazin-2-yl)-5-chlorophenyl]-4-morpholinyl]-2-propen-1-oneVividion NRF2 inhibitor lead