Halofuginone (hydrochloride)
(Synonyms: 盐酸卤夫酮/常山酮盐酸盐) 目录号 : GC43804An inhibitor of TGF-β signaling and TH17 differentiation
Cas No.:1217623-74-9
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Halofuginone is a halogenated derivative of febrifugine, a natural quinazolinone-containing compound found in the Chinese herb D. febrifuga. It has antimalarial and anticoccidial actions. In mammals, halofuginone at 10 ng/ml down-regulates Smad3, blocking TGF-β signaling and preventing both the differentiation of fibroblasts to myofibroblasts and the transitioning of epithelial cells to mesenchymal cells. Through this action, halofuginone blocks fibrosis and tumor progression in a variety of different models. This compound also competitively inhibits prolyl-tRNA synthetase (Ki = 18.3 nM), activating the amino acid starvation response. This prevents the differentiation of TH17 cells, blunting an autoimmune response.
Cas No. | 1217623-74-9 | SDF | |
别名 | 盐酸卤夫酮/常山酮盐酸盐 | ||
Canonical SMILES | BrC1=C(Cl)C=C2C(N=CN(CC(C[C@H]3NCCC[C@@H]3O)=O)C2=O)=C1.Cl | ||
分子式 | C16H17BrClN3O3•HCl | 分子量 | 451.1 |
溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.2168 mL | 11.084 mL | 22.168 mL |
5 mM | 0.4434 mL | 2.2168 mL | 4.4336 mL |
10 mM | 0.2217 mL | 1.1084 mL | 2.2168 mL |
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Halofuginone attenuates osteoarthritis by inhibition of TGF-β activity and H-type vessel formation in subchondral bone
Ann Rheum Dis 2016 Sep;75(9):1714-21.PMID:26470720DOI:10.1136/annrheumdis-2015-207923.
Objectives: Examine whether osteoarthritis (OA) progression can be delayed by Halofuginone in anterior cruciate ligament transection (ACLT) rodent models. Methods: 3-month-old male C57BL/6J (wild type; WT) mice and Lewis rats were randomised to sham-operated, ACLT-operated, treated with vehicle, or ACLT-operated, treated with Halofuginone. Articular cartilage degeneration was graded using the Osteoarthritis Research Society International (OARSI)-modified Mankin criteria. Immunostaining, flow cytometry, RT-PCR and western blot analyses were conducted to detect relative protein and RNA expression. Bone micro CT (μCT) and CT-based microangiography were quantitated to detect alterations of microarchitecture and vasculature in tibial subchondral bone. Results: Halofuginone attenuated articular cartilage degeneration and subchondral bone deterioration, resulting in substantially lower OARSI scores. Specifically, we found that proteoglycan loss and calcification of articular cartilage were significantly decreased in halofuginone-treated ACLT rodents compared with vehicle-treated ACLT controls. Halofuginone reduced collagen X (Col X), matrix metalloproteinase-13 and A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS 5) and increased lubricin, collagen II and aggrecan. In parallel, halofuginone-attenuated uncoupled subchondral bone remodelling as defined by reduced subchondral bone tissue volume, lower trabecular pattern factor (Tb.pf) and increased thickness of subchondral bone plate compared with vehicle-treated ACLT controls. We found that Halofuginone exerted protective effects in part by suppressing Th17-induced osteoclastic bone resorption, inhibiting Smad2/3-dependent TGF-β signalling to restore coupled bone remodelling and attenuating excessive angiogenesis in subchondral bone. Conclusions: Halofuginone attenuates OA progression by inhibition of subchondral bone TGF-β activity and aberrant angiogenesis as a potential preventive therapy for OA.
Halofuginone, a promising drug for treatment of pulmonary hypertension
Br J Pharmacol 2021 Sep;178(17):3373-3394.PMID:33694155DOI:10.1111/bph.15442.
Background and purpose: Halofuginone is a febrifugine derivative originally isolated from Chinese traditional herb Chang Shan that exhibits anti-hypertrophic, anti-fibrotic and anti-proliferative effects. We sought to investigate whether Halofuginone induced pulmonary vasodilation and attenuates chronic hypoxia-induced pulmonary hypertension (HPH). Experimental approach: Patch-clamp experiments were conducted to examine the activity of voltage-dependent Ca2+ channels (VDCCs) in pulmonary artery smooth muscle cells (PASMCs). Digital fluorescence microscopy was used to measure intracellular Ca2+ concentration in PASMCs. Isolated perfused and ventilated mouse lungs were used to measure pulmonary artery pressure (PAP). Mice exposed to hypoxia (10% O2 ) for 4 weeks were used as model of HPH for in vivo experiments. Key results: Halofuginone increased voltage-gated K+ (Kv ) currents in PASMCs and K+ currents through KCNA5 channels in HEK cells transfected with KCNA5 gene. HF (0.03-1 μM) inhibited receptor-operated Ca2+ entry in HEK cells transfected with calcium-sensing receptor gene and attenuated store-operated Ca2+ entry in PASMCs. Acute (3-5 min) intrapulmonary application of Halofuginone significantly and reversibly inhibited alveolar hypoxia-induced pulmonary vasoconstriction dose-dependently (0.1-10 μM). Intraperitoneal administration of Halofuginone (0.3 mg·kg-1 , for 2 weeks) partly reversed established PH in mice. Conclusion and implications: Halofuginone is a potent pulmonary vasodilator by activating Kv channels and blocking VDCC and receptor-operated and store-operated Ca2+ channels in PASMCs. The therapeutic effect of Halofuginone on experimental PH is probably due to combination of its vasodilator effects, via inhibition of excitation-contraction coupling and anti-proliferative effects, via inhibition of the PI3K/Akt/mTOR signalling pathway.
Prospects of Halofuginone as an antiprotozoal drug scaffold
Drug Discov Today 2022 Sep;27(9):2586-2592.PMID:35636724DOI:10.1016/j.drudis.2022.05.020.
Halofuginone is a clinically active derivative of febrifugine that was first isolated from the Chinese herb Dichroa febrifuga. The beneficial biological effects of Halofuginone on various diseases including parasitic diseases, cancer, fibrosis, and autoimmune disorders have been investigated. Halofuginone has reduced toxic side effects when compared to febrifugine, an advantage that has led to the commercial availability of halofuginone-based antiparasitic drugs for animal use, and to human clinical trials for the treatment of tumors and fibrosis. This review summarizes advances in determining the mechanism of action of Halofuginone, focusing on its antiparasitic role in malaria, cryptosporidiosis, coccidiosis, toxoplasmosis, and leishmaniasis. We discuss mechanistic insights into Halofuginone's primary mode of action which involves inhibition of the prolyl-tRNA synthetase enzyme, which is crucial in protein synthesis. Halofuginone exemplifies the untapped wealth of plant-derived compounds in disease therapeutics.
Glutamyl-Prolyl-tRNA Synthetase Regulates Proline-Rich Pro-Fibrotic Protein Synthesis During Cardiac Fibrosis
Circ Res 2020 Aug 28;127(6):827-846.PMID:32611237DOI:10.1161/CIRCRESAHA.119.315999.
Rationale: Increased protein synthesis of profibrotic genes is a common feature in cardiac fibrosis and heart failure. Despite this observation, critical factors and molecular mechanisms for translational control of profibrotic genes during cardiac fibrosis remain unclear. Objective: To investigate the role of a bifunctional ARS (aminoacyl-tRNA synthetase), EPRS (glutamyl-prolyl-tRNA synthetase) in translational control of cardiac fibrosis. Methods and results: Results from reanalyses of multiple publicly available data sets of human and mouse heart failure, demonstrated that EPRS acted as an integrated node among the ARSs in various cardiac pathogenic processes. We confirmed that EPRS was induced at mRNA and protein levels (≈1.5-2.5-fold increase) in failing hearts compared with nonfailing hearts using our cohort of human and mouse heart samples. Genetic knockout of one allele of Eprs globally (Eprs+/-) using CRISPR-Cas9 technology or in a Postn-Cre-dependent manner (Eprsflox/+; PostnMCM/+) strongly reduces cardiac fibrosis (≈50% reduction) in isoproterenol-, transverse aortic constriction-, and myocardial infarction (MI)-induced heart failure mouse models. Inhibition of EPRS using a PRS (prolyl-tRNA synthetase)-specific inhibitor, Halofuginone, significantly decreases translation efficiency (TE) of proline-rich collagens in cardiac fibroblasts as well as TGF-β (transforming growth factor-β)-activated myofibroblasts. Overexpression of EPRS increases collagen protein expression in primary cardiac fibroblasts under TGF-β stimulation. Using transcriptome-wide RNA-Seq and polysome profiling-Seq in halofuginone-treated fibroblasts, we identified multiple novel Pro-rich genes in addition to collagens, such as Ltbp2 (latent TGF-β-binding protein 2) and Sulf1 (sulfatase 1), which are translationally regulated by EPRS. SULF1 is highly enriched in human and mouse myofibroblasts. In the primary cardiac fibroblast culture system, siRNA-mediated knockdown of SULF1 attenuates cardiac myofibroblast activation and collagen deposition. Overexpression of SULF1 promotes TGF-β-induced myofibroblast activation and partially antagonizes anti-fibrotic effects of Halofuginone treatment. Conclusions: Our results indicate that EPRS preferentially controls translational activation of proline codon rich profibrotic genes in cardiac fibroblasts and augments pathological cardiac remodeling. Graphical Abstract: A graphical abstract is available for this article.
Halofuginone and muscular dystrophy
Histol Histopathol 2011 Jan;26(1):135-46.PMID:21117034DOI:10.14670/HH-26.135.
Muscular dystrophies (MDs) include different inherited diseases that all result in progressive muscle degeneration, impaired locomotion and often premature death. The major focus of MD research has been on alleviating the primary genetic deficit - using gene therapy and myoblast-transfer approaches to promote expression of the deficient or mutated genes in the muscle fibers. Although promising, these approaches have not yet entered into clinical practice and unfortunately for MD patients, there is currently no cure. Thus, the development of complementary and supportive therapies that slow disease progression and improve patients' quality of life is critically important. The main features of MDs are sarcolemmal instability and increased myofiber vulnerability to mechanical stress, resulting in myofiber degeneration. Fibrosis, with progressive replacement of muscle tissue, is a prominent feature in some MDs, preventing complete regeneration and hampering muscle functions. TGFβ is the leading candidate for activating fibroblasts and eliciting overproduction of extracellular matrix (ECM) proteins. Halofuginone, an inhibitor of Smad3 phosphorylation downstream of TGFβ signaling, inhibits the activation of fibroblasts and their ability to synthesize ECM, regardless of their origin or location. In animal models of MDs with prominent muscle fibrosis, Halofuginone treatment has resulted in both prevention of collagen production in young animals and resolution of established fibrosis in older ones: the reduction in muscle collagen content was associated with improved muscle histopathology and major improvements in muscle function. Recently, these halofuginone-dependent improvements were also observed in MD with minor fibrosis involvement, probably due to a direct effect of Halofuginone on muscle cells, resulting in myotube fusion that is dependent on Akt and MAPK pathway activation. In summary, Halofuginone improves muscle histopathology and muscle functions in various MDs, via inhibition of muscle fibrosis on the one hand, and increased myotube fusion on the other.