Cevidoplenib
(Synonyms: SKI-O-703) 目录号 : GC63429
Cevidoplenib（SKI-O-703）是一种具有口服活性的选择性脾脏酪氨酸激酶 （Syk）抑制剂。
Cas No.:1703788-21-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment [1]: | |
Cell lines | Mouse primary B cells |
Preparation method | Mouse primary B cells were labeled with CP670, and stimulated with either anti-IgM mAb, CD40L and IL-4 or LPS for 72 h in the presence or absence of Cevidoplenib (0-5μM) and tofacitinib at the indicated concentrations. |
Reaction Conditions | 0-5μM; 72 h |
Applications | Cevidoplenib inhibits B-cell receptor (BCR) cross-linking-induced cell proliferation in a concentration-dependent manner. |
Animal experiment [2]: | |
Animal models | Male WT or Mincle KO mice |
Preparation method | After control diet feeding for 5 days, mice received 10 mg/kg Cevidoplenib or vehicle control by oral administration every 10 days during EtOH-diet feeding. |
Dosage form | 10mg/kg; p.o. |
Applications | EtOH-fed mice treated with Cevidoplenib had reduced liver neutrophil infiltration, liver damage, and steatosis. |
References: | |
Cevidoplenib (SKI-O-703) is an orally active and selective spleen tyrosine kinase (Syk) inhibitor[1]. Syk is a crucial regulatory molecule in the signal transduction pathways involved in autoimmune diseases such as immune thrombocytopenia (ITP)[2]. Cevidoplenib is also the mesylate form of SKI-O-592, with an IC50 value of 6.2 nM for Syk[3].
In vitro, Cevidoplenib (0-5μM) treated primary mouse B cells for 72 hours, inhibiting B cell receptor (BCR) cross-linking-induced cell proliferation in a concentration-dependent manner. It increased the proportion of early and late apoptotic cells. This cytotoxic effect was stronger when B cells were activated by anti-IgM mAb compared to LPS activation[3].
In vivo, Cevidoplenib (84 mg/kg) was administered orally to mice with systemic lupus erythematosus (SLE), significantly reducing levels of IgG autoantibodies, proteinuria, and glomerulonephritis. It also decreased the levels of germinal centers (GC) involved in humoral immune responses and serum B cell-activating factor (BAFF) signaling from the TNF family[3]. Cevidoplenib (42, 84 mg/kg) was administered orally to mice with antiphospholipid syndrome (APS), significantly reducing antiphospholipid antibody (APLs) levels and preventing myocardial arteriolar thrombosis in mice[4]. Cevidoplenib (10 mg/kg) was administered orally to mice with alcoholic liver disease (ALD), effectively reducing hepatic neutrophil infiltration, inhibiting liver injury, and steatosis[5].
References:
[1] Provan D, Newland A C. Investigational drugs for immune thrombocytopenia[J]. Expert Opinion on Investigational Drugs, 2022, 31(7): 715-727.
[2] Cooper N, Ghanima W, Hill Q A, et al. Recent advances in understanding spleen tyrosine kinase (SYK) in human biology and disease, with a focus on fostamatinib[J]. Platelets, 2023, 34(1): 2131751.
[3] Cho S, Jang E, Yoon T, et al. A novel selective spleen tyrosine kinase inhibitor SKI-O-703 (cevidoplenib) ameliorates lupus nephritis and serum-induced arthritis in murine models[J]. Clinical and Experimental Immunology, 2023, 211(1): 31-45.
[4] Jang E, Hwang H, Yoon T, et al. S307: CEVIDOPLENIB (SKI-O-703), A NOVEL SYK INHIBITOR, REDUCES ANTIPHOSPHOLIPID ANTIBODY TITERS AND PREVENTS INTRAMYOCARDIAL SMALL ARTERIAL THROMBOSIS IN A MOUSE MODEL OF ANTIPHOSPHOLIPID SYNDROME[J]. HemaSphere, 2023, 7(S3): e3562913.
[5] Kim J W, Roh Y S, Jeong H, et al. Spliceosome-associated protein 130 exacerbates alcohol-induced liver injury by inducing NLRP3 inflammasome–mediated IL-1β in mice[J]. The American journal of pathology, 2018, 188(4): 967-980.
Cevidoplenib（SKI-O-703）是一种具有口服活性的选择性脾脏酪氨酸激酶 （Syk）抑制剂[1]。Syk是参与免疫性血小板减少症（ITP）等自身免疫性疾病发病机制的信号转导途径的重要调节分子[2]。Cevidoplenib也是SKI-O-592 的甲磺酸形式，SKI-O-592对Syk的IC50值为6.2 nM[3]。
在体外，Cevidoplenib（0-5μM）处理小鼠原代B细胞72 h，以浓度依赖性方式抑制了B细胞受体（BCR）交联诱导的细胞增殖，增加了早期和晚期凋亡细胞的比例，并且当B细胞被抗IgM mAb激活时，这种细胞毒性作用比被LPS激活时更强[3]。
在体内，Cevidoplenib（84mg/kg）通过口服治疗系统性红斑狼疮(SLE)小鼠，显著降低了IgG自身抗体、蛋白尿和肾小球肾炎的水平，还降低了参与体液免疫应答的生发中心（GC）和TNF家族的血清B细胞活化因子（BAFF）信号传导[3]。Cevidoplenib（42、84mg/kg）通过口服治疗抗磷脂综合征（APS）小鼠，显著降低了抗磷脂抗体（APLs）水平，预防了小鼠心肌内小动脉血栓的形成[4]。Cevidoplenib（10mg/kg）通过口服治疗酒精性肝病(ALD)小鼠，有效减少了肝脏中性粒细胞浸润，抑制了肝损伤和脂肪变性[5]。
| Cas No. | 1703788-21-9 | SDF | |
| 别名 | SKI-O-703 | ||
| 分子式 | C25H27N7O3 | 分子量 | 473.53 |
| 溶解度 | DMSO:35 mg/mL | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1118 mL | 10.559 mL | 21.118 mL |
| 5 mM | 0.4224 mL | 2.1118 mL | 4.2236 mL |
| 10 mM | 0.2112 mL | 1.0559 mL | 2.1118 mL |
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A novel selective spleen tyrosine kinase inhibitor SKI-O-703 (Cevidoplenib) ameliorates lupus nephritis and serum-induced arthritis in murine models
Clin Exp Immunol 2023 Mar 8;211(1):31-45.PMID:36346114DOI:10.1093/cei/uxac096.
Spleen tyrosine kinase (Syk) plays a pivotal role in the activation of B cells and innate inflammatory cells by transducing immune receptor-triggered signals. Dysregulated activity of Syk is implicated in the development of antibody-mediated autoimmune diseases including systemic lupus erythematosus (SLE) and rheumatoid arthritis, but the effect of Syk inhibition on such diseases remains to be fully evaluated. We have developed a novel selective Syk inhibitor, SKI-O-592, and its orally bioavailable salt form, SKI-O-703 (Cevidoplenib). To examine the efficacy of SKI-O-703 on the progression of SLE, New Zealand black/white mice at the autoimmunity-established phase were administrated orally with SKI-O-703 for 16 weeks. Levels of IgG autoantibody, proteinuria, and glomerulonephritis fell significantly, and this was associated with hypoactivation of follicular B cells via the germinal center. In a model of serum-transferred arthritis, SKI-O-703 significantly ameliorated synovitis, with fewer neutrophils and macrophages infiltrated into the synovial tissue. This effect was recapitulated when mice otherwise refractory to anti-TNF therapy were treated by TNF blockade combined with a suboptimal dose of SKI-O-703. These results demonstrate that the novel selective Syk inhibitor SKI-O-703 attenuates the progression of autoantibody-mediated autoimmune diseases by inhibiting both autoantibody-producing and autoantibody-sensing cells.