Activation of the fibroblast growth factor receptor FGFR4 by fibroblast growth factor (FGF)19 drives hepatocellular carcinoma (HCC), a disease with few effective treatment options. H3B-6527 is a highly selective and orally available small molecule inhibitor of FGFR4 with an IC50 less than 1.2 nM. In a HCC cell line Hep3B, H3B-6527 (1 nM; 24 h) caused a robust increase in CYP7A1 transcripts suggesting strong inhibition of the FGFR4 pathway by H3B-6527. Further, the levels of pERK1/2 decreased in a dose-dependent manner with maximal inhibition occurring at 100 nM of H3B-6527. In the Hep3B human HCC xenograft mouse model, treatment with H3B-6527 inhibited Hep3B xenograft growth, with the 300 and 100 mg/kg twice-daily doses significantly inhibiting growth and inducing CR (complete regression) or PR (partial regression) in 8 of 8 and 6 of 8 of mice, respectively (TGI (tumor growth inhibition) of 115 and 109%, P<0.05, for the 300 and 100 mg/kg treatment groups, respectively). H3B-6527 is currently undergoing evaluation in a phase I clinical trial in HCC[3].
作用机制
H3B-6527 has an acrylamide group that forms a covalent bond via Michael addition with the Cys552 on FGFR4, present in the hinge region of the ATP-binding pocket[2].
H3B-6527 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HN12 cells
5 μM
Suppressed Vimentin protein levels, thereby inhibiting cell migration
J Exp Clin Cancer Res. 2021 Mar 10;40(1):93.
3T3 cells
0.1 nM –10 µM
5 days
Evaluate the inhibitory effect of H3B-6527 on FGFR4 N535K and FGFR4 V550L, results showed that H3B-6527 was effective against FGFR4 N535K but not against FGFR4 V550L.
NPJ Precis Oncol. 2021 Jul 16;5(1):66.
KYSE150
1 μM
3 days
Inhibited proliferation, invasion, and migration of KYSE150 cells, and altered epithelial-mesenchymal transition markers.
Thorac Cancer. 2018 Dec;9(12):1687-1698.
KYSE450
1 μM
3 days
Inhibited proliferation, invasion, and migration of KYSE450 cells, and altered epithelial-mesenchymal transition markers.
Thorac Cancer. 2018 Dec;9(12):1687-1698.
CAMA1
1.0 µM
14 days
H3B-6527 promoted the growth of FGF2-treated cells in FGFR1-amplified CAMA1 cells and inhibited FGF2-induced cell proliferation.
Breast Cancer Res. 2024 Mar 29;26(1):54.
Human HepG2 cells
20 ng/mL
30 min
To investigate the effect of FGFR4 inhibition on NPC1L1 protein degradation, results showed that H3B-6527 rescued FGF19-induced NPC1L1 protein decay.
Lipids Health Dis. 2022 Oct 8;21(1):97.
H3B-6527 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NSG mice
Orthotopic tongue tumor model
Intratumoral injection
10 μM(50 μl)
Every 3 days for 2 weeks
Evaluated the inhibitory effect of H3B-6527 on lymph node metastasis of MT-LE HN30 cells, showing that H3B-6527 significantly reduced lymph node metastasis
J Exp Clin Cancer Res. 2021 Mar 10;40(1):93.
BALB/c nude mice
Esophageal squamous cell carcinoma (ESCC) tumor xenograft model
Intraperitoneal injection
10 mg/kg
Once daily for 20 days
H3B-6527 significantly inhibited the growth of ESCC xenograft tumors.
Thorac Cancer. 2018 Dec;9(12):1687-1698.
C57BL/6 mice
Left ventricular hypertrophy model
Intraperitoneal injection
10 mg/kg
Daily until 12 weeks of age
To evaluate the effect of H3B-6527 on left ventricular hypertrophy, the results showed that H3B-6527 did not improve left ventricular hypertrophy.
Front Endocrinol (Lausanne). 2023 Dec 19;14:1276664
Mice
NPC1L1hepatic-OE mice
Intraperitoneal injection
5 mg/kg
Once daily for 7 days
To investigate the effect of H3B-6527 on hepatic NPC1L1 protein degradation in LD-fed mice, results showed that H3B-6527 partially restored bile cholesterol reabsorption efficiency.
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