ISM7594 is an orally active FGFR2/3 inhibitor demonstrating broad-spectrum antiproliferative capabilities in cancer cell lines with FGFR2 or FGFR3 alterations, such as amplification, fusion, and mutation (e.g., BaF3-TEL-FGFR2-V564F with an IC50 of 0.067 nM, BaF3-TEL-FGFR2-V564I with an IC50 of 2 nM). It inhibits tumor growth in a dose-dependent manner and is suitable for research on advanced solid tumors with FGFR2/3 abnormalities.

FGFR1:118.4 nM

ISM7594 demonstrates significant inhibitory activity against FGFR2 (IC 50 = 1.7 nM) and FGFR3 (IC 50 = 12.4 nM), surpassing the activity of the control compound RE1, within a concentration range of 0.01-1000 nM. It effectively inhibits various FGFR2 mutants such as V564I (IC 50 = 4.4 nM) and V564F (IC 50 = 0.22 nM). The compound shows high epithelial permeability and a low efflux rate in Caco-2 assays. Additionally, ISM7594, ranging from 0.152-1000 nM over 2 hours, suppresses phosphorylation of FGFR and ERK in gastric adenocarcinoma (SNU-16) and bladder cancer (RT4) cells. Over 72 hours, at 10 μM, ISM7594 exhibits antiproliferative effects in various mutated cell lines, including BaF3-FGFR2/3 mutations and several types of cancer cells: gastric (KATO-III, SNU-16, SNU1), breast (SUM52PE, MCF-7), endometrial (AN3CA, MFE280), bladder (RT112-84, RT4, UM-UC-14, T24, UM-UC-3), multiple myeloma (OPM-2, U266), and liver (Li-7) cells, with differing IC 50 values. With a concentration of 1000 nM, ISM7594 selectively inhibits FGFR1 with an inhibition rate of 92.9%.

ISM7594 (3-30 mg/kg, orally administered once or twice daily for 21 days) inhibits tumor growth in a dose-dependent manner in mouse models with subcutaneous xenografts driven by FGFR2 or FGFR3.