SBFI-26
目录号 : GC39236SBFI-26是脂肪酸结合蛋白FABP5和FABP7的选择性和竞争性抑制剂,SBFI-26与FABP5的典型配体结合袋结合,Kjs为0。
Cas No.:1541207-06-0
Sample solution is provided at 25 µL, 10mM.
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- Purity: >98.00%
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Cell experiment [1]: | |
Cell lines |
HeLa cells |
Preparation Method |
Cells were transfected with the PPAR reporter system, incubated with GW7647, rosiglitazone, or SBFI-26 for 6 hrs, followed by measurement of luciferase and β-galactosidase activity using a luminometer as described. |
Reaction Conditions |
10uM SBFI-26 for 6 hrs |
Applications |
Confirming its selectivity for FABPs, SBFI-26 failed to reduce AEA uptake in cells bearing a knockdown of FABP5, the main FABP expressed in HeLa cells. Additionally, SBFI-26 does not inhibit FAAH. Collectively,SB-FI-26 is a selective FABP inhibitor. |
Animal experiment [2]: | |
Animal models |
Male C57Bl6 mice (22-30 g) |
Preparation Method |
SBFI-26 (20 mg/kg) was dissolved in ethanol∶emulphor∶saline (1∶1∶18), requiring sonication and gentle heating for solubilization, and administered 45 min prior to injection of carrageenan. |
Dosage form |
20 mg/kg SBFI-26 for 45min |
Applications |
SBFI-26 (20 mg/kg) significantly reduced carrageenan-induced thermal hyperalgesia and paw edema |
References: [1]: Berger WT, Ralph BP, et,al. Targeting fatty acid binding protein (FABP) anandamide transporters - a novel strategy for development of anti-inflammatory and anti-nociceptive drugs. PLoS One. 2012;7(12):e50968. doi: 10.1371/journal.pone.0050968. Epub 2012 Dec 7. PMID: 23236415; PMCID: PMC3517626. |
SBFI-26 is a selective and competitive inhibitor of fatty acid binding proteins FABP5 and FABP7, SBFI-26 binds to the canonical ligand-binding pocket of FABP5[2],with Kjs of 0.9 μM and 0.4 μM for FABP5 and ABP7, respectively. SBFI-26 produces anti-nociceptive and anti-inflammatory effects[1,2].
The FABP inhibitor SBFI-26 does not decrease the amplitude of EPSCs and is a weak agonist of PPARα and PPARγ receptors. Confirming its selectivity for FABPs, SBFI-26failed to reduce AEA uptake in cells bearing a knockdown of FABP5, the main FABP expressed in HeLa cells. Additionally, SBFI-26 does not inhibit FAAH. Collectively, SBFI-26 is a selective FABP inhibitor[1].
SBFI-26 produces analgesic and anti-inflammatory effects in mice, SBFI-26 (20 mg/kg) significantly reduced carrageenan-induced thermal hyperalgesia and paw edema[1]. FABP5 was the only one dramatically upregulated along with increased protein expression in the established PH-LHD mouse model. Inhibition of FABP5 by SBFI-26 injection abrogated pulmonary artery remodelling in PH-LHD and improved cardiac function[3].
References:
[1]: Berger WT, Ralph BP, et,al. Targeting fatty acid binding protein (FABP) anandamide transporters - a novel strategy for development of anti-inflammatory and anti-nociceptive drugs. PLoS One. 2012;7(12):e50968. doi: 10.1371/journal.pone.0050968. Epub 2012 Dec 7. PMID: 23236415; PMCID: PMC3517626.
[2]: Hsu HC, Tong S, et,al. The Antinociceptive Agent SBFI-26 Binds to Anandamide Transporters FABP5 and FABP7 at Two Different Sites. Biochemistry. 2017 Jul 11;56(27):3454-3462. doi: 10.1021/acs.biochem.7b00194. Epub 2017 Jun 28. PMID: 28632393; PMCID: PMC5884075.
[3]: Lei Q, Yu Z, et,al. Fatty acid-binding protein 5 aggravates pulmonary artery fibrosis in pulmonary hypertension secondary to left heart disease via activating wnt/β-catenin pathway. J Adv Res. 2022 Sep;40:197-206. doi: 10.1016/j.jare.2021.11.011. Epub 2021 Nov 26. PMID: 36100327; PMCID: PMC9481948.
SBFI-26 是脂肪酸结合蛋白 FABP5 和 FABP7 的选择性和竞争性抑制剂,SBFI-26 与 FABP5[2] 的典型配体结合口袋结合,Kjs 为 0.9 μM FABP5 和 ABP7 分别为 0.4 μM。 SBFI-26 具有抗伤害和抗炎作用[1,2]。
FABP 抑制剂 SBFI-26 不会降低 EPSC 的振幅,并且是 PPARα 和 PPARγ 受体的弱激动剂。证实其对 FABP 的选择性,SBFI-26 未能减少具有 FABP5 敲低的细胞中的 AEA 摄取,FABP5 是 HeLa 细胞中表达的主要 FABP。此外,SBFI-26 不抑制 FAAH。总的来说,SBFI-26 是一种选择性 FABP 抑制剂[1]。
SBFI-26 在小鼠体内产生镇痛和抗炎作用,SBFI-26 (20 mg/kg) 显着减轻角叉菜胶诱导的热痛觉过敏和爪水肿[1]。在已建立的 PH-LHD 小鼠模型中,FABP5 是唯一一种随着蛋白质表达的增加而显着上调的基因。 SBFI-26 注射液抑制 FABP5 可消除 PH-LHD 肺动脉重构并改善心功能[3]。
Cas No. | 1541207-06-0 | SDF | |
Canonical SMILES | O=C([C@H]1[C@@H](C2=CC=CC=C2)[C@H](C(O)=O)[C@@H]1C3=CC=CC=C3)OC4=CC=CC5=C4C=CC=C5.[Relative stereochemistry] | ||
分子式 | C28H22O4 | 分子量 | 422.47 |
溶解度 | DMSO: 100 mg/mL (236.70 mM) | 储存条件 | Store at -20°C, protect from light |
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Shipping Condition | 评估样品解决方案:配备蓝冰进行发货。所有其他可用尺寸:配备RT,或根据请求配备蓝冰。 |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.367 mL | 11.8352 mL | 23.6703 mL |
5 mM | 0.4734 mL | 2.367 mL | 4.7341 mL |
10 mM | 0.2367 mL | 1.1835 mL | 2.367 mL |
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给药剂量 | mg/kg | 动物平均体重 | g | 每只动物给药体积 | ul | 动物数量 | 只 | |||
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工作液浓度: mg/ml;
DMSO母液配制方法: mg 药物溶于 μL DMSO溶液(母液浓度 mg/mL,
体内配方配制方法:取 μL DMSO母液,加入 μL PEG300,混匀澄清后加入μL Tween 80,混匀澄清后加入 μL saline,混匀澄清。
1. 首先保证母液是澄清的;
2.
一定要按照顺序依次将溶剂加入,进行下一步操作之前必须保证上一步操作得到的是澄清的溶液,可采用涡旋、超声或水浴加热等物理方法助溶。
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The Antinociceptive Agent SBFI-26 Binds to Anandamide Transporters FABP5 and FABP7 at Two Different Sites
Biochemistry 2017 Jul 11;56(27):3454-3462.PMID:28632393DOI:10.1021/acs.biochem.7b00194.
Human FABP5 and FABP7 are intracellular endocannabinoid transporters. SBFI-26 is an α-truxillic acid 1-naphthyl monoester that competitively inhibits the activities of FABP5 and FABP7 and produces antinociceptive and anti-inflammatory effects in mice. The synthesis of SBFI-26 yields several stereoisomers, and it is not known how the inhibitor binds the transporters. Here we report co-crystal structures of SBFI-26 in complex with human FABP5 and FABP7 at 2.2 and 1.9 Å resolution, respectively. We found that only (S)-SBFI-26 was present in the crystal structures. The inhibitor largely mimics the fatty acid binding pattern, but it also has several unique interactions. Notably, the FABP7 complex corroborates key aspects of the ligand binding pose at the canonical site previously predicted by virtual screening. In FABP5, SBFI-26 was unexpectedly found to bind at the substrate entry portal region in addition to binding at the canonical ligand-binding pocket. Our structural and binding energy analyses indicate that both R and S forms appear to bind the transporter equally well. We suggest that the S enantiomer observed in the crystal structures may be a result of the crystallization process selectively incorporating the (S)-SBFI-26-FABP complexes into the growing lattice, or that the S enantiomer may bind to the portal site more rapidly than to the canonical site, leading to an increased local concentration of the S enantiomer for binding to the canonical site. Our work reveals two binding poses of SBFI-26 in its target transporters. This knowledge will guide the development of more potent FABP inhibitors based upon the SBFI-26 scaffold.
Fatty acid-binding protein 5 aggravates pulmonary artery fibrosis in pulmonary hypertension secondary to left heart disease via activating wnt/β-catenin pathway
J Adv Res 2022 Sep;40:197-206.PMID:36100327DOI:10.1016/j.jare.2021.11.011.
Introduction: Pulmonary hypertension secondary to left heart disease (PH-LHD) is a common and fatal disease. However, no effective therapeutic targets have been identified. Objectives: Here, we set out to illustrate the functional role and underlying mechanisms of fatty acid-binding protein 5 (FABP5) in PH-LHD development. Methods: We performed a systematic analysis of datasets GSE84704 and GSE16624 to identify differentially expressed genes and then constructed protein-protein interaction network for significant modules. Potential target genes in the modules were validated by RT-qPCR and western blot in a PH-LHD mouse model. PH-LHD or sham mice were treated with FABP5 antagonist SBFI-26 or DMSO for 28 days. The role of FABP5 on cardiac function was determined by echocardiography, its impact on pulmonary vascular remodelling were evaluated with right heart catheter, histological analysis and western blot. In vitro, primary pulmonary adventitial fibroblasts were used to investigate the pro-fibrotic mechanisms involving in FABP5. Results: FABP5 was the only one dramatically upregulated along with increased protein expression in the established PH-LHD mouse model. Inhibition of FABP5 by SBFI-26 injection abrogated pulmonary artery remodelling in PH-LHD and improved cardiac function. In vitro, SBFI-26 or FABP5 siRNA blunted the TGF-β1-induced fibrotic response in cultured pulmonary adventitial fibroblasts. Mechanistically, FABP5 knockdown inhibited GSK3β phosphorylation and increased β-catenin phosphorylation. The wnt/β-catenin agonist SKL2001 diminished the antifibrotic effect of FABP5 knockdown on pulmonary adventitial fibroblasts under TGF-β1 stimulation. Conclusion: FABP5 is an important mediator of pulmonary artery remodelling and a potential therapeutic target for PH-LHD.
Identification of Fatty Acid Binding Protein 5 Inhibitors Through Similarity-Based Screening
Biochemistry 2019 Oct 22;58(42):4304-4316.PMID:31539229DOI:10.1021/acs.biochem.9b00625.
Fatty acid binding protein 5 (FABP5) is a promising target for development of inhibitors to help control pain and inflammation. In this work, computer-based docking (DOCK6 program) was employed to screen ∼2 M commercially available compounds to FABP5 based on an X-ray structure complexed with the small molecule inhibitor SBFI-26 previously identified by our group (also through virtual screening). The goal was discovery of additional chemotypes. The screen resulted in the purchase of 78 candidates, which led to the identification of a new inhibitor scaffold (STK-0) with micromolar affinity and apparent selectivity for FABP5 over FABP3. A second similarity-based screen resulted in three additional hits (STK-15, STK-21, STK-22) from which preliminary SAR could be derived. Notably, STK-15 showed comparable activity to the SBFI-26 reference under the same assay conditions (1.40 vs 0.86 μM). Additional molecular dynamics simulations, free energy calculations, and structural analysis (starting from DOCK-generated poses) revealed that R enantiomers (dihydropyrrole scaffold) of STK-15 and STK-22 have a more optimal composition of functional groups to facilitate additional H-bonds with Arg109 of FABP5. This observation suggests enantiomerically pure compounds could show enhanced activity. Overall, our study highlights the utility of using similarity-based screening methods to discover new inhibitor chemotypes, and the identified FABP5 hits provide a strong starting point for future efforts geared to improve activity.
Endocannabinoid metabolism and transport as targets to regulate intraocular pressure
Exp Eye Res 2020 Dec;201:108266.PMID:32979397DOI:10.1016/j.exer.2020.108266.
Cannabinoids are part of an endogenous signaling system found throughout the body, including the eye. Hepler and Frank showed in the early 1970s that plant cannabinoids can lower intraocular pressure (IOP), an effect since shown to occur via cannabinoid CB1 and GPR18 receptors. Endocannabinoids are synthesized and metabolized enzymatically. Enzymes implicated in endocannabinoids breakdown include monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), but also ABHD12, NAAA, and COX-2. Inhibition of MAGL activity raises levels of the endocannabinoid 2-arachidonoyl glycerol and substantially lowers IOP. Blocking other cannabinoid metabolizing enzymes or cannabinoid transporters may similarly contribute to lowering IOP and so serve as therapeutic targets for treating glaucoma. We have tested blockers for several cannabinoid-metabolizing enzymes and transporters (FABP5 and membrane reuptake) for their ability to alter ocular pressure in a murine model of IOP. Of FAAH, ABHD12, NAAA, and COX2, only FAAH was seen to play a role in regulation of IOP. Only the FAAH blocker URB597 lowered IOP, but in a temporally, diurnally, and sex-specific manner. We also tested two blockers of cannabinoid transport (SBFI-26 and WOBE437), finding that each lowered IOP in a CB1-dependent manner. Though we see a modest, limited role for FAAH, our results suggest that MAGL is the primary cannabinoid-metabolizing enzyme in regulating ocular pressure, thus pointing towards a role of 2-arachidonoyl glycerol. Interestingly, inhibition of cannabinoid transport mechanisms independent of hydrolysis may prove to be an alternative strategy to lower ocular pressure.
Downregulation of FABP5 Suppresses the Proliferation and Induces the Apoptosis of Gastric Cancer Cells Through the Hippo Signaling Pathway
DNA Cell Biol 2021 Aug;40(8):1076-1086.PMID:34160301DOI:10.1089/dna.2021.0370.
Fatty acid binding protein 5 (FABP5) has been reported to play an important role in various cancers. We found that high FABP5 expression was associated with poor histological differentiation and vascular invasion. High FABP5 expression indicated a poor prognosis. Downregulation of FABP5 suppressed cell proliferation, cell migration and invasion, and induced cell apoptosis. Bioinformatic analysis revealed that the Hippo signaling pathway was related to FABP5. We found that overexpression of yes-associated protein 1 (YAP1) could partially reverse the effect of FABP5 knockdown on growth and apoptosis. The FABP5 inhibitor SBFI-26 suppressed the proliferation and promoted the apoptosis of gastric cancer (GC) cells and interfered with the Hippo signaling pathway by inhibiting YAP1. Our data suggested that FABP5 might act as a potential target associated with the Hippo signaling pathway for GC treatment.