Adipocyte fatty acid binding protein (aFABP) is a 14.6 kDa cytosolic protein located in adipocytes and macrophages, and assists in the intracellular transport of fatty acids. It is one of a class of fatty acid binding proteins (FABPs) that are found predominately in the liver, heart, intestine, and connective tissues[5]. BMS-309403 is a potent, selective and cell-permeable inhibitor of FABP4 with a Ki of less than 2 nM, which exhibits Ki values 250 nM for FABP3 and 350 nM for FABP5[5]. BMS-309403 interacts with the fatty-acid-binding pocket within the interior of the protein and competitively inhibits the binding of endogenous fatty acids. Treatment with BMS-309403 significantly decreased MCP-1 production from THP-1 macrophages in a dose- and time-dependent manner[6]. BMS-309403 stimulates glucose uptake in C2C12 myotubes in a temporal and dose dependent manner via activation of AMP-activated protein kinase (AMPK) signaling pathway but independent of FABPs[7]. The extent of atherosclerotic lesion area in the proximal aorta is significantly reduced in the BMS-309403-treated group compared with vehicle-treated controls in both the early and late intervention studies[6]. A 6 weeks treatment with BMS-309403 improves endothelial function, phosphorylated and total eNOS (endothelial nitric oxide synthase) and reduced plasma triglyceride levels. In cultured human microvascular endothelial cells, lipid-induced aFABP expression is associated with reduced phosphorylated eNOS and NO production and is reversed by BMS-309403[8].
BMS-309403 细胞实验
Cell Line
Concentration
Treated Time
Description
References
DRG neurons
10 µM
15 minutes
BMS309403 inhibited CAY10455 uptake in DRG neurons, reducing AEA uptake
Neurobiol Dis. 2013 Oct;58:19-28.
Human umbilical vein endothelial cells (HUVECs)
20 µM
24 hours
BMS309403 significantly inhibited the tube formation, proliferation, migration, and invasion of HUVECs induced by rhFABP4 or M1-polarized macrophage supernatant.
Bone Res. 2022 Jun 22;10(1):45.
Fibroblast-like synoviocytes (FLSs)
20 µM
24 hours
BMS309403 significantly inhibited the proliferation, migration, and invasion of FLSs induced by rhFABP4 or M1-polarized macrophage supernatant.
Bone Res. 2022 Jun 22;10(1):45.
SKOV3ip1 cells
20 µM
24 hours
BMS309403 treatment resulted in cell cycle arrest, increasing the number of cells in the G1 phase and reducing the number of cells in the S phase.
Cancer Res. 2020 Apr 15;80(8):1748-1761.
RBE cells
20 µM
24 hours
BMS309403 significantly suppressed the adipose-induced CCA invasion and migration in vitro and reversed the effects of adipose tissue extracts on EMT-related protein expression.
J Exp Clin Cancer Res. 2017 Dec 13;36(1):183.
Hccc-9810 cells
20 µM
24 hours
BMS309403 significantly suppressed the adipose-induced migration and invasion of Hccc-9810 cells.
J Exp Clin Cancer Res. 2017 Dec 13;36(1):183.
Human Microvascular Endothelial Cells (HMECs)
50 µM
24 hours
BMS-309403 reversed the palmitate-induced reduction in eNOS phosphorylation and cGMP production, indicating its beneficial effect on endothelial function.
Br J Pharmacol. 2011 Apr;162(7):1564-76.
HepG2 cells
10, 30, 50 µM
24 hours
BMS309403 reversed the promoting effects of FABP4 on HepG2 cell proliferation and migration, and increased active caspase 3 expression.
Oncogene. 2019 Apr;38(16):3033-3046.
HuH7 cells
10, 30, 50 µM
24 hours
BMS309403 reversed the promoting effects of FABP4 on HuH7 cell proliferation.
Oncogene. 2019 Apr;38(16):3033-3046.
Thp-1 cells
50 µM
24 hours
Inhibition of A-FABP almost reversed PA-induced macrophage apoptosis, indicating that A-FABP plays a critical role in PA-induced macrophage apoptosis.
Front Immunol. 2018 Jan 30;9:81.
BV-2 cells
50 µM
24 hours
To evaluate the effect of BMS309403 on LPS-induced inflammatory response in BV-2 cells, results showed that BMS309403 significantly reduced ROS and TNF-α production.
J Neuroimmune Pharmacol. 2023 Sep;18(3):448-461.
Primary mouse microglia
50 µM
24 hours
To evaluate the effect of BMS309403 on LPS-induced inflammatory response in primary mouse microglia, results showed that BMS309403 significantly reduced TNF-α production.
J Neuroimmune Pharmacol. 2023 Sep;18(3):448-461.
Mouse renal tubular epithelial cells (TCMK-1)
10 µM
30 minutes
Inhibition of FABP4, alleviating LPS-induced inflammation and apoptosis
Cell Death Dis. 2022 Apr 11;13(4):333.
Rat neutrophils
10 µM
30 minutes
After BMS-309403 treatment, FABP4 expression in rat neutrophils decreased, and apoptosis was reduced.
Cell Mol Life Sci. 2024 Oct 25;81(1):438.
Mouse neutrophils
10 µM
30 minutes
After BMS-309403 treatment, FABP4 expression in mouse neutrophils decreased, and apoptosis was reduced.
Cell Mol Life Sci. 2024 Oct 25;81(1):438.
C1498 cells
30 µM
48 hours
BMS309403 treatment led to downregulation of DNMT1, reduction of global DNA methylation, and restoration of p15INK4B expression
Leukemia. 2018 Apr;32(4):865-873.
MV4-11 cells
30 µM
48 hours
BMS309403 treatment led to downregulation of DNMT1, reduction of global DNA methylation, and restoration of p15INK4B expression
Leukemia. 2018 Apr;32(4):865-873.
Kasumi-1 cells
30 µM
48 hours
BMS309403 treatment led to downregulation of DNMT1, reduction of global DNA methylation, and restoration of p15INK4B expression
Leukemia. 2018 Apr;32(4):865-873.
Bone marrow-derived macrophages (BMDMs)
2.5 ng/ml
5 days
To investigate the role of FABP4 in TGF-b1-induced transition of BMDMs into myofibroblasts, results showed that FABP4 deficiency significantly inhibited TGF-b1-induced a-SMA expression.
Front Immunol. 2020 Sep 30;11:566535.
COS-7 cells
20–100 µM
5 minutes
BMS-309403 significantly reduced AEA uptake and hydrolysis in COS-7 cells, with a maximal inhibition of 48%.
Proc Natl Acad Sci U S A. 2009 Apr 14;106(15):6375-80.
N18TG2 cells
20–100 µM
5 minutes
BMS-309403 significantly reduced AEA uptake and hydrolysis in N18TG2 cells, with a maximal inhibition of 57%.
Proc Natl Acad Sci U S A. 2009 Apr 14;106(15):6375-80.
PE01 and PE04 cells
20 µM
72 hours
BMS309403 significantly increased the sensitivity of PE04 cells to carboplatin.
Cancer Res. 2020 Apr 15;80(8):1748-1761.
BMS-309403 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Apolipoprotein E-deficient mice (ApoE-/-)
Oral gavage
15 mg/kg/day
Once daily for 6 weeks
BMS-309403 improved endothelium-dependent relaxations, increased phosphorylated and total eNOS levels, and reduced plasma triglyceride levels.
Br J Pharmacol. 2011 Apr;162(7):1564-76.
Mice
Syngeneic orthotopic mouse model
Oral
20 mg/kg
Six days a week for 4 weeks
BMS309403 significantly reduced metastatic tumor burden and increased tumor sensitivity to carboplatin.
Cancer Res. 2020 Apr 15;80(8):1748-1761.
C57BL/6J mice
CLP or LPS-induced septic acute kidney injury model
Oral
40 mg/kg/d
Once daily for 3 days
Inhibition of FABP4, alleviating septic acute kidney injury
Cell Death Dis. 2022 Apr 11;13(4):333.
C57BL/6 mice
Unilateral ureteral obstruction (UUO) model
Oral
40 mg/kg/day
Once daily, during the UUO surgery period
To evaluate the effect of BMS-309403 on UUO-induced kidney fibrosis, the results showed that BMS-309403 significantly attenuated kidney fibrosis and lipid deposition.
Cell Death Dis. 2021 Jun 3;12(6):572
BALB/c Nude mice
Heterotopic and orthotopic xenografted model
Intraperitoneal injection
45 mg/kg
Twice a week for 3 weeks
BMS309403 significantly reduced tumor growth in heterotopic and orthotopic xenografted models and increased tumor necrosis.
Oncogene. 2019 Apr;38(16):3033-3046.
C57BL/6 J mice
Antigen-induced arthritis (AIA) model
Intraperitoneal injection
5 mg/kg
Twice a week for 4 or 8 weeks
BMS309403 significantly reduced FABP4 expression in synovial M1-polarized macrophages and serum, suppressed synovitis, angiogenesis, and cartilage degradation, thereby alleviating experimental RA progression.
Bone Res. 2022 Jun 22;10(1):45.
C57BL/6 mice
Cecal ligation and puncture (CLP)-induced sepsis model
Intraperitoneal injection
5 mg/kg
Administered 2 days before modeling
BMS-309403 treatment exacerbated CLP-induced lung injury, while neutrophil depletion alleviated the promotion of ARDS development by BMS-309403.
Cell Mol Life Sci. 2024 Oct 25;81(1):438.
C57BL/6 mice
High-fat diet-induced steatotic liver transplantation model
Intraperitoneal injection
5 mg/kg
Single dose, 1 hour before transplantation
To evaluate the protective effect of BMS-309403 on ischemia-reperfusion injury in the steatotic liver transplantation model, results showed that BMS-309403 reduced hepatocyte apoptosis, decreased serum transaminase levels, and alleviated oxidative stress damage.
Cell Mol Life Sci. 2024 Feb 10;81(1):83
C57BL/6 mice
Leukemia model
Intraperitoneal injection
5 mg/kg and 10 mg/kg
Initial dose of 5 mg/kg, leukemia cells injected 12 hours later, 3 additional doses within 3 days, followed by two doses of 10 mg/kg
BMS309403 significantly reduced leukemic burden, prolonged survival time, and restored granulocytic differentiation of bone marrow cells
Leukemia. 2018 Apr;32(4):865-873.
C57BL/6J mice
Unilateral ureteral obstruction (UUO) model
Oral
50 mg/kg/day
Once daily for 7 days
To investigate the effect of BMS309403 on attenuating renal fibrosis in the UUO model, results showed that BMS309403 significantly reduced renal interstitial inflammation and fibrosis.
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