GFH547

GFH547 is an orally bioavailable, small molecule inhibitor developed by GenFleet Therapeutics. It acts as a panRAS(on) inhibitor with broad-spectrum anti-tumor activity, designed to target cancers harboring multiple RAS mutations—including KRAS (G12A, G12C, G12V, G12R, G12S, or G13D), NRAS (G12D or Q61L), and HRAS (Q61H). The drug works by hijacking intracellular cyclophilin A (CypA) to block oncogenic RAS proteins in their active forms. This mechanism allows GFH547 to overcome resistance mechanisms that limit the efficacy of SIIP-based KRAS inhibitors such as sotorasib and adagrasib. Preclinical studies have shown potent tumor-suppressive effects across various cancer cell lines with diverse RAS mutations and also in some cell lines with EGFR or FGFR2/3 alterations. Notably, it remains effective against models carrying acquired resistance to other KRAS inhibitors and demonstrates high selectivity without significant off-target kinase inhibition[2][1][3].