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• 产品描述： Zimlovisertib (PF-06650833) is a potent, selective and orally active inhibitor of interleukin-1 receptor associated kinase 4 (IRAK4) with IC50s of 0.2 and 2.4 nM in the cell and PBMC assay, respectively. Zimlovisertib is used to treat diseases such as rheumatoid arthritis, lupus, and lymphomas

• 靶点： IRAK4:0.2 nM (IC50)

• 体外研究： The kinome selectivity profile of Zimlovisertib (Compound 40) is assessed in a panel of 278 kinases (Invitrogen) at 200 nM inhibitor concentration using the ATP Km for each kinase. Approximately 100% inhibition is observed for IRAK4. Lactam Zimlovisertib is assessed in a whole cell functional VEGF2R assay (PAE-KDR cell line). No activity is observed at concentrations up to and including 30 μM. In a voltage clamp assay, Zimlovisertib inhibits hERG current by 25% at 100 μM. The ability of Zimlovisertib to inhibit five major CYP450 enzymes is assessed using pooled human liver microsomes and probe substrates for the CYP450 enzymes. At a concentration of 3 μM of Zimlovisertib, less than 5% inhibition of CYPs 1A2, 2C8, 2C9, 2D6, and 3A4 is observed. Lactam Zimlovisertib is examined for time dependent inhibition effects on six major CYP450 enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, and 2D6) using pooled human liver microsomes and probe substrates. At 100 μM of Zimlovisertib, no time dependent CYP inhibition is observed. The potential induction of CYP3A by Zimlovisertib is assessed using cryopreserved human hepatocytes and afforded a 4.4-fold increase in mRNA at 10 μM

• 体内研究： Zimlovisertib (0.3-30 mg/kg; oral administration; for 2.5 hours; male Sprague-Dawley rats) treatment significantly inhibits LPS-induced TNF-α in a dose dependent manner. Mean exposures of Zimlovisertib in plasma are 2.1 nM, 7.7 nM, 19 nM and 150 nM free, respectively, at 2.5 hours after oral administration of Zimlovisertib at 0.3, 1, 3, and 30 mg/kg. The fraction unbound in rat plasma of Zimlovisertib is 0.3. Animal Model: Male Sprague-Dawley rats Dosage: 0.1 mg/kg, 1 mg/kg, 3 mg/kg, 30 mg/kg Administration: Oral administration; for 2.5 hours Result: Significantly inhibited LPS-induced TNF-α in a dose dependent manner.

• 参考文献：
  1. Lee KL, et al. Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design. J Med Chem. 2017 Jul 13;60(13):5521-5542. 2. Seganish WM. Inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4): a patent review (2012-2015). Expert Opin Ther Pat. 2016 Aug;26(8):917-32.

• 溶解性： Soluble  in  DMSO

• 保存条件： -20℃

• 配置溶液浓度参考：
  

  	1mg	5mg	10mg
  1 mM	2.767 ml	13.836 ml	27.673 ml
  5 mM	0.553 ml	2.767 ml	5.535 ml
  10 mM	0.277 ml	1.384 ml	2.767 ml
  50 mM	0.055 ml	0.277 ml	0.553 ml

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本计算器可帮助您计算出特定溶液中溶质的质量、溶液浓度和体积之间的关系，公式为：

质量 (mg) = 浓度 (mM) x 体积 (mL) x 分子量 (g/mol)

• pg ng μg mg g kg =
  fM pM nM μM mM M *
  nL μL mL L *