Effect of fiin2 on gene expression of Hep3B cells
Fibroblast growth factor receptor (FGFR) inhibitors have emerged as an important class of targeted therapies in oncology, targeting key pathways associated with tumor growth, angiogenesis, and resistance to conventional treatments. FIIN-2, the first irreversible covalent pan-FGFR inhibitor, has shown promise in overcoming resistance due to gatekeeper mutations; however, its selectivity and molecular mechanisms in tumors remain poorly understood. In this study, an FIIN-2 chemical probe was designed and synthesized to identify both established and novel targets in hepatocellular carcinoma (HCC) via chemoproteomic profiling. An integrative multi-omics approach, including chemoproteomic, phosphoproteomic, transcriptomic, and proteomic analyses, is utilized to elucidate the full spectrum of target proteins, signaling pathways, and downstream effectors regulated by FIIN-2 in HCC. This study greatly advances the understanding of FIIN-2's on- and off-target effects, offering a comprehensive view of its molecular mechanisms in cancer cells. The integrative multi-omics approach provides a valuable framework for the development and optimization of covalent kinase inhibitors. Overall design: RNA-seq profiling of Hep3B cells treated with 1um fiin2 or dmso