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

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...

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Autores principales:	Yunju Nam, Injae Shin, Younghoon Kim, SeongShick Ryu, Namdoo Kim, Eunhye Ju, Taebo Sim
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	FGFR4 kinase HCC FGFR4 inhibitor GNF-7 SAR Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/e355c3f209df48bb95c0874512458e1d
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spelling	oai:doaj.org-article:e355c3f209df48bb95c0874512458e1d2021-12-04T04:33:26ZAnti-cancer effects of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one derivatives on hepatocellular carcinoma harboring FGFR4 activation1476-558610.1016/j.neo.2021.11.011https://doaj.org/article/e355c3f209df48bb95c0874512458e1d2022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S1476558621001019https://doaj.org/toc/1476-5586Hepatocellular 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.Yunju NamInjae ShinYounghoon KimSeongShick RyuNamdoo KimEunhye JuTaebo SimElsevierarticleFGFR4 kinaseHCCFGFR4 inhibitorGNF-7SARNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENNeoplasia: An International Journal for Oncology Research, Vol 24, Iss 1, Pp 34-49 (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	FGFR4 kinase HCC FGFR4 inhibitor GNF-7 SAR Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	FGFR4 kinase HCC FGFR4 inhibitor GNF-7 SAR Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Yunju Nam Injae Shin Younghoon Kim SeongShick Ryu Namdoo Kim Eunhye Ju Taebo Sim Anti-cancer effects of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one derivatives on hepatocellular carcinoma harboring FGFR4 activation
description	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.
format	article
author	Yunju Nam Injae Shin Younghoon Kim SeongShick Ryu Namdoo Kim Eunhye Ju Taebo Sim
author_facet	Yunju Nam Injae Shin Younghoon Kim SeongShick Ryu Namdoo Kim Eunhye Ju Taebo Sim
author_sort	Yunju Nam
title	Anti-cancer effects of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one derivatives on hepatocellular carcinoma harboring FGFR4 activation
title_short	Anti-cancer effects of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one derivatives on hepatocellular carcinoma harboring FGFR4 activation
title_full	Anti-cancer effects of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one derivatives on hepatocellular carcinoma harboring FGFR4 activation
title_fullStr	Anti-cancer effects of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one derivatives on hepatocellular carcinoma harboring FGFR4 activation
title_full_unstemmed	Anti-cancer effects of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one derivatives on hepatocellular carcinoma harboring FGFR4 activation
title_sort	anti-cancer effects of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1h)-one derivatives on hepatocellular carcinoma harboring fgfr4 activation
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/e355c3f209df48bb95c0874512458e1d
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Anti-cancer effects of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one derivatives on hepatocellular carcinoma harboring FGFR4 activation

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