SAFit1
目录号 : GC33699
SAFit1 是一种 FK506 结合蛋白 51(FKBP51)特异性抑制剂,其 Ki 值为 4 ± 0.3nM。
Cas No.:1643125-32-9
Sample solution is provided at 25 µL, 10mM.
SAFit1 is a FK506 binding protein 51 (FKBP51)-specific inhibitor with a Ki value of 4 ± 0.3nM[1]. The selective inhibition of FKBP51 using SAFfit1 has emerged as a possible treatment for chronic pain, obesity-induced diabetes, or depression[2][3].
In vitro, SAFit1 (1-1000nM) effectively stimulated neurite growth in two neuronal cell lines, specifically the mouse N2a line and the human SH-SY5Y line, as well as in primary hippocampal neurons. The active concentration range of SAFit1 is very wide[1]. The NanoBRET assay shows that SAFit1 (1-100000nM) treated HEK293T cells transiently expressing FKBP51-NLuc for 2h dose-dependently competed with a fluorescent NanoBRET tracer, which indicated that SAFit1 was able to engage FKBP51 inside cells. SAFit1 (0.4, 0.2, 1μM) incubated murine microglia SIM-A9 cells for 16h could engage FKBP51 in cells and inhibited IKKα phosphorylation in a dose-dependent manner[4]. A375 melanoma incubated in the presence of 20nM SAFit1 for 5h decreased transcript and protein levels of the receptor type I of TGF-β (TβRI) and reduced the protein expression of phosphorylated (p)-Smad2,3. SAFit1 finally inhibited FKBP51-dependent TGF-β pro-tumoral function in vitro[5].
In vivo, mice received SAFit1 (30mg/kg) and SAFit2 (30mg/kg) as a cassette dose orally in a pharmacokinetic study. The experimental results showed that the maximum concentration (Cmax) of SAFit1 in mice was 1467ng/mL, and the time to reach Cmax was 0.5 hours, indicating that SAFIT1 was absorbed quickly in the gastrointestinal tract[6].
References:
[1] Gaali S, Kirschner A, Cuboni S, et al.Selective inhibitors of the FK506-binding protein 51 by induced fit. Nat Chem Biol. 2015 Jan;11(1):33-7.
[2] Sidibeh C O, Pereira M J, Abalo X M,et al.FKBP5 expression in human adipose tissue: potential role in glucose and lipid metabolism, adipogenesis and type 2 diabetes.Endocrine. 2018 Oct;62(1):116-128.
[3] Knaup F H, Meyners C, Sugiarto W O, et al.Structure-Based Discovery of a New Selectivity-Enabling Motif for the FK506-Binding Protein 51. J Med Chem. 2023 Apr 27;66(8):5965-5980.
[4] Voll A M, Meyners C, Taubert M C, et al. Macrocyclic FKBP51 Ligands Define a Transient Binding Mode with Enhanced Selectivity. Angew Chem Int Ed Engl. 2021 Jun 7; 60(24): 13257-13263.
[5] Marrone L, Giacomo V D, Malasomma C, et al. Exploring the potential of selective FKBP51 inhibitors on melanoma: an investigation of their in vitro and in vivo effects. Cell Death Discov. 2025 Apr 3;11(1):138.
[6] Gabani B B, Sulochana S P, Siddesh A H,et al. Validated LC-MS/MS Method for Simultaneous Quantitation of SAFit-1 and SAFit-2 in Mice Plasma: Application to a Pharmacokinetic Study. Drug Res (Stuttg). 2020 Jul;70(7):325-332.
SAFit1是一种FK506结合蛋白51(FKBP51)特异性抑制剂,其Ki值为4 ± 0.3nM[1]。FKBP51的选择性抑制已成为治疗慢性疼痛、肥胖引起的糖尿病或抑郁症的一种可能方法[2][3]。
在体外,SAFit1(1-1000nM)有效刺激了两种神经元细胞系(具体为小鼠N2a细胞系和人SH-SY5Y细胞系)以及原代海马神经元的神经突生长。SAFit1的有效浓度范围非常广[1]。NanoBRET分析显示,用SAFit1(1-100000nM)处理瞬时表达FKBP51-NLuc的HEK293T细胞2小时后,剂量依赖性地与荧光NanoBRET示踪剂竞争,这表明SAFit1能够在细胞内结合FKBP51。用SAFit1(0.4、0.2、1μM)孵育小鼠小胶质细胞SIM-A9 16小时后,可以在细胞中结合FKBP51,并以剂量依赖方式抑制IKKα磷酸化[4]。
在体内,小鼠在药代动力学研究中口服接受了SAFit1(30mg/kg)和SAFit2(30mg/kg)作为组合剂量。实验结果表明,小鼠体内SAFit1的最大浓度(Cmax)为1467ng/mL,达到Cmax的时间为0.5小时,这表明SAFIT1在胃肠道中被迅速吸收[5]。
Cell experiment [1]: | |
Cell lines | murine microglia SIM-A9 cell |
Preparation Method | For the preparation of whole-cell lysates, confluent SIM-A9 cell cultures treated with the SAFit1 for 16h. Subsequently, supernatants of cell lysis were prepared for an SDS-PAGE system and analyzed by immunoblotting. |
Reaction Conditions | 0.4, 0.2, 1μM; 16h |
Applications | SAFit1 interfered with the cellular functions of FKBP51 and inhibited IKKα phosphorylation. |
Animal experiment [2]: | |
Animal models | male Balb/C mice |
Preparation Method | Twelve male Balb/C mice were housed at Jubilant Animal House facility (having 12/12h light/dark cycles with controlled humidity and temperature) for seven days before performing pharmacokinetic study. Mice were fasted for 4h (during the fasting period animals had free access to water) on the day of pharmacokinetic study. Mice received SAFit1 (30mg/kg) and SAFit2 (30mg/kg) as a cassette dose orally. Blood samples (100μL) were collected at pre-determined time points (0.083, 0.17, 0.25, 0.5, 1, 2, 4, 8, 10 and 24h) from retro-orbital plexus. |
Dosage form | 30mg/kg; oral administration.; one dose |
Applications | Following oral administration SAFit1 maximum concentration (Cmax) in plasma (1467ng/mL) attained at 0.5h (Tmax, time to reach Cmax) indicating the rapid absorption from gastrointestinal tract. The AUC0-∞ (area under curve from time zero to infinity) was found to be 1851ng × h/mL for SAFit1. |
References: |
Cas No. | 1643125-32-9 | SDF | |
Canonical SMILES | O=C(N1[C@@H](CCCC1)C(O[C@@H](C2=CC(OCC(O)=O)=CC=C2)CCC3=CC(OC)=C(OC)C=C3)=O)[C@@H](C4CCCCC4)C5=CC(OC)=C(OC)C(OC)=C5 | ||
分子式 | C42H53NO11 | 分子量 | 747.87 |
溶解度 | Methanol : 125 mg/mL (167.14 mM);DMSO : 62.5 mg/mL (83.57 mM);Water : < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
1 mM | 1.3371 mL | 6.6857 mL | 13.3713 mL |
5 mM | 0.2674 mL | 1.3371 mL | 2.6743 mL |
10 mM | 0.1337 mL | 0.6686 mL | 1.3371 mL |
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Quality Control & SDS
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- Purity: >98.00%
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