DGY-09-192

DGY-09-192 is a proteolysis-targeting chimera (PROTAC) designed to selectively degrade fibroblast growth factor receptors 1 and 2 (FGFR1 and FGFR2). It is composed of the pan-FGFR tyrosine kinase inhibitor BGJ398 (infigratinib) conjugated to a ligand for the von Hippel-Lindau (VHL) E3 ubiquitin ligase. By recruiting VHL to FGFR1/2, DGY-09-192 facilitates the ubiquitination and subsequent proteasomal degradation of these receptors. This approach is particularly effective against nuclear FGFR1, which is often resistant to standard tyrosine kinase inhibitors and contributes to antiestrogen resistance in ER+/FGFR1-amplified breast cancer. Preclinical studies have shown that DGY-09-192 can overcome endocrine resistance and inhibit growth in cancer cells with FGFR1/2 amplifications or activating mutations, such as FGFR2 N549K and K659E.