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Seletalisib

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Chemical Structure| 1362850-20-1 同义名 : UCB5857
CAS号 : 1362850-20-1
货号 : A369020
分子式 : C23H14ClF3N6O
纯度 : 99%+
分子量 : 482.845
MDL号 : MFCD28963973
存储条件：

粉末 Keep in dark place,Sealed in dry,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 85 mg/mL(176.04 mM)，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：
生物活性
靶点

  • p110γ

    PI3Kγ, IC50:282 nM

  • p110δ

    PI3Kδ, IC50:12 nM
描述 Phosphoinositide 3-kinases (PI3K) are key signaling enzymes regulating cellular survival, development, and function. Expression of the PI3Kδ isoform is largely restricted to leukocytes and it plays a key role in immune cell development and function. Seletalisib is a potent, ATP-competitive, and selective PI3Kδ inhibitor, which is able to block protein kinase B (AKT) phosphorylation following activation of the B-cell receptor in a B-cell line. Seletalisib inhibits T-cell differentiation to Th1, Th2, and Th17 subtypes. Additionally, Seletalisib inhibits B-cell proliferation and cytokine release. In human whole blood assays, Seletalisib inhibits CD69 expression upon B-cell activation and anti-IgE-mediated basophil degranulation[3]. Seletalisib was found to be actively transported by rodent and human P-gp in vitro (transfected LLC-PK1 cells; Km of ca. 20 µM), with minimal or no affinity for the other tested transporters. P-gp restricts the brain disposition of seletalisib while having minimal effect on its intestinal absorption. Restricted brain penetration was also observed in cynomolgus monkeys (single oral dosing at 30 mg kg-1) using brain microdialysis and cerebrospinal fluid sampling (Kp,uu of 0.09 and 0.24, respectively). In vitro, CsA inhibited the active transport of seletalisib with an IC50 of 0.13 µM. In rats, co-administration of high doses of CsA (bolus iv followed by continuous infusion) increased the brain distribution of seletalisib (single oral dosing at 5 mg kg-1)[4]. In vitro, seletalisib inhibited the production of pro-inflammatory cytokines, including IL-17A and IL-17F, from peripheral blood mononuclear cells (PBMCs), T helper 17 (Th17) cells as well as γδ-T cells and mucosal-associated invariant T cells. This inhibition resulted in decreased inflammatory activation of HDF in co-culture systems. Seletalisib was also efficacious in inhibiting SpA PBMCs and synovial fluid mononuclear cells (SFMCs) from producing pro-inflammatory cytokines[5].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.07mL

0.41mL

0.21mL

10.36mL

2.07mL

1.04mL

20.71mL

4.14mL

2.07mL
参考文献

[1]Allen RA, Brookings DC, et al. Seletalisib: Characterization of a Novel, Potent, and Selective Inhibitor of PI3Kδ. J Pharmacol Exp Ther. 2017 Apr 25. pii: jpet.116.237347.

[2]Helmer E, Watling M, et al. First-in-human studies of seletalisib, an orally bioavailable small-molecule PI3Kδ inhibitor for the treatment of immune and inflammatory diseases. Eur J Clin Pharmacol. 2017 May;73(5):581-591.

[3]Rodger A Allen,et al. Seletalisib: Characterization of a Novel, Potent, and Selective Inhibitor of PI3K δ. J Pharmacol Exp Ther. 2017. 361(3), 429-440.

[4]Jean-Marie Nicolas,et al. Eur J Pharm Sci. 2020. 142, 105122.

[5]Sijia Chen,et al. Selective targeting of PI3Kδ suppresses human IL-17-producing T cells and innate-like lymphocytes and may be therapeutic for IL-17-mediated diseases. J Autoimmun. 2020. 111, 102435.