Anti-cancer effects of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one derivatives on hepatocellular carcinoma harboring FGFR4 activation

Yunju Nam, Injae Shin, Younghoon Kim, Seong Shick Ryu, Namdoo Kim, Eunhye Ju, Taebo Sim

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)34-49
Number of pages16
JournalNeoplasia (United States)
Issue number1
Publication statusPublished - 2022 Jan

Bibliographical note

Funding Information:
This research was supported by Basic Science Research Program (NRF-2021R1A2C3011992) from the National Research Foundation in Korea, Korea Institute of Science and Technology (KIST), Brain Korea 21 Project, and the KU-KIST Graduate School of Converging Science and Technology Program.

Publisher Copyright:
© 2021

All Science Journal Classification (ASJC) codes

  • Cancer Research


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