GFH603

GFH603 is a molecular glue-like allosteric activator of the KEAP1-CUL3 E3 ligase complex, developed by GenFleet Therapeutics for the treatment of NRF2-activated tumors. It works by restoring the function of the KEAP1-CUL3 E3 ligase, which is often disrupted in cancers such as esophageal squamous cell carcinoma (ESCC), lung squamous cell carcinoma (LUSC), and lung adenocarcinoma (LUAD) due to mutations in NFE2L2, KEAP1, or CUL3. By promoting the assembly of the KEAP1-CUL3 complex, GFH603 induces the degradation of the oncogenic transcription factor NRF2. Preclinical studies have demonstrated potent anti-tumor activity as a monotherapy and synergistic effects when combined with pan-RAS inhibitors in KRAS/KEAP1 co-mutant models. ADMET profiling has shown favorable characteristics, including high oral bioavailability.