DGY-09-192 is a PROTAC FGFR1/2 degrader with DC50 values of 4.35 nM for FGFR1 and 70 nM for FGFR2. It selectively degrades wild-type FGFR1/2 and various FGFR2 fusion proteins, including FGFR2-PHGDH and FGFR2-OPTN. In both in vitro and in vivo studies, DGY-09-192 inhibits downstream FGFR signaling pathways by reducing the phosphorylation of FRS2Y196 and ERK1/2T202/Y204.

DGY-09-192 induces dose-dependent degradation of FGFR2 in KATO III cells with DC50 at 70 nM and Dmax at 74% when used at concentrations from 0.01 to 10 μM over 6 hours. In CCLP-1-FP cells (expressing FGFR2-PHGDH fusion protein) and ICC13-7 cells (expressing FGFR2-OPTN fusion protein), DGY-09-192 at 0.1-1 μM for 24 hours results in dose-dependent degradation of FGFR2-PHGDH and FGFR2-OPTN fusion proteins. Furthermore, DGY-09-192 at 0.1-10 μM for 16 hours degrades FGFR1 effectively in CCLP1 cells that overexpress FGFR1, with a DC50 of 4.35 nM and Dmax of 85%. It also exhibits antiproliferative activity in KATO III cells (IC50 = 1 nM), CCLP1 cells (IC50 = 17 nM), ICC13-7 cells (IC50 = 40 nM), and CCLP-FP cells (IC50 = 8 nM) over 72 hours at concentrations ranging from 0.0001 to 100000 nM. Lastly, DGY-09-192 at 50 nM for 4-8 hours continuously inhibits the downstream FGFR2 signaling pathway in CCLP1-FP cells.

DGY-09-192 administered at 20-40 mg/kg via intraperitoneal injection once daily for 6 days induces a reduction in the levels of FGFR2-PHGDH fusion protein and decreases the phosphorylation of downstream markers FRS2 (Y196) and ERK1/2 (T202/Y204) in the CCLP1-FGFR2-PHGDH xenograft tumor model.