1. Anti-cancer effects of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one derivatives on hepatocellular carcinoma harboring FGFR4 activation
- Author
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Yunju Nam, Injae Shin, Younghoon Kim, SeongShick Ryu, Namdoo Kim, Eunhye Ju, and Taebo Sim
- Subjects
Models, Molecular ,Cancer Research ,Carcinoma, Hepatocellular ,FGFR, fibroblast growth factor receptor ,Molecular Conformation ,Antineoplastic Agents ,Apoptosis ,Pyrimidinones ,FGFR4 kinase ,KLB, klotho beta ,Structure-Activity Relationship ,Cell Movement ,Cell Line, Tumor ,Humans ,Receptor, Fibroblast Growth Factor, Type 4 ,HCC ,RC254-282 ,Cell Proliferation ,Original Research ,Dose-Response Relationship, Drug ,Molecular Structure ,FGFR4 inhibitor ,Liver Neoplasms ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cell Cycle Checkpoints ,digestive system diseases ,FGF, fibroblast growth factor ,GNF-7 ,HCC, hepatocellular carcinoma ,EMT, epithelial-mesenchymal transition ,Signal Transduction ,PARP, poly (ADP-ribose) polymerase ,SAR - Abstract
Highlights • GNF-7, a multi-targeted kinase inhibitor, is highly potent against FGFR4. • GNF-7 and SIJ1263 are highly potent on Ba/F3 cells with wtFGFR4 or mtFGFR4. • GNF-7 and SIJ1263 are highly potent on HCC cells with FGFR4 activation. • GNF-7 and SIJ1263 strongly block FGFR signaling and induce apoptosis in HCC cells. • GNF-7 and SIJ1263 strongly suppress migration/invasion/AIG of HCC cells., Hepatocellular carcinoma (HCC) is disease with a high mortality rate and limited treatment options. Alterations of fibroblast growth factor receptor 4 (FGFR4) has been regarded as an oncogenic driver for HCC and a promising target for HCC therapeutics. Herein, we report that GNF-7, a multi-targeted kinase inhibitor, and its derivatives including SIJ1263 (IC50 < 1 nM against FGFR4) are highly potent FGFR4 inhibitors and are capable of strongly suppressing proliferation of HCC cells and Ba/F3 cells transformed with wtFGFR4 or mtFGFR4. Compared with known FGFR4 inhibitors, both GNF-7 and SIJ1263 possess much higher (up to 100-fold) anti-proliferative activities via FGFR signaling blockade and apoptosis on HCC cells. Especially, SIJ1263 is 80-fold more potent (GI50 = 24 nM) on TEL-FGFR4 V550E Ba/F3 cells than BLU9931, which suggests that SIJ1263 would be effective for overriding drug resistance. In addition, both substances strongly suppress migration/invasion and colony formation of HCC cells. It is worth noting that SIJ1263 is superior to GNF-7 with regards to the fact that activities of SIJ1263 are higher than those of GNF-7 in all assays performed in this study. Collectively, this study provides insight into designing highly potent FGFR4 inhibitors capable of potentially overcoming drug-resistance for the treatment of HCC patients.
- Published
- 2022