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• 产品描述： URMC-099 is an orally bioavailable and potent mixed lineage kinase type 3 (MLK3) (IC50=14 nM) inhibitor with with excellent blood-brain barrier penetration properties.

• 靶点： LRRK2:11 nM (IC50);FLT3:4 nM (IC50);FLT1:39 nM (IC50);ABL1 (T315I):3 nM (IC50);ABL1:6.8 nM (IC50);SGK;67 nM (IC50);SGK1:201 nM (IC50);AurA:108 nM (IC50);AurB:123 nM (IC50);AurC:290 nM (IC50);IKKβ:257 nM (IC50);IKKα:591 nM (IC50);TNFα:460 nM (IC50);ROCK1:1030 nM (IC50);ROCK2:111 nM (IC50);CDK1:1125 nM (IC50);CDK2:1180 nM (IC50);TRKA:85 nM (IC50);c-MET:177 nM (IC50);TRKB:217 nM (IC50);IGF1R:307 nM (IC50);LCK:333 nM (IC50);MEKK2:661 nM (IC50);SYK:731 nM (IC50);AMPK:1512 nM (IC50);JNK1:3280 nM (IC50);SRC:4330 n

• 体外研究：
  The effect of URMC-099 (URMC099) on the in vitro growth of the “brain homing” MDA-MB-231 BR cells expressing eGFP (eGFP8.4) and their parental cell line, MDA-MB-231 is tested. The cells are treated with either 200 nM URMC-099 or vehicle alone. Cells treated with URMC-099 grow at a similar rate to those treated with vehicle. Cell viability is >99% in all cases。

• 体内研究：
  URMC-099 has moderate terminal elimination half-life (t1/2=1.92 h, 2.14 h and 2.72 h for C57 BL/6 mice (10 mg/kg, oral dosing), C57 BL/6 mice (2.5 mg/kg, iv), C57 BL/6 mice (10 mg/kg, iv))[1]. The effect of URMC-099 (URMC099) on tumor formation in vivo is analyzed using a well characterized mouse xenograft model of breast cancer brain metastasis. For these experiments, eGFP8.4 cells are inoculated into the left ventricle of immunodeficient nu/nu mice; animals are then treated with either URMC-099 (10 mg/kg) or vehicle alone, every 12 hours for 20 days. This dose of URMC-099 is chosen because it has been shown to be sufficient to effectively inhibit MLK3 in mice, with good penetration of the blood-brain barrier and potent inhibition of the phosphorylation of Jun N-terminal kinase (JNK) in brain tissue. On day 21 the mice are sacrificed and number of BM is assessed. Fifteen mice are used for each treatment group. BM are detected in 60% of mice, which is consistent with previous studies using this xenograft model by other investigators. URMC-099 treatment significantly (p<0.05, two-tailed t-test) increases the total number of brain metastasis (BM) in mice. For micrometastases, the pattern is similar to that observed for total BM. The number of macrometastases is statistically indistinguishable between mice treated with URMC-099 or vehicle。

• 参考文献：
  1. Goodfellow VS, et al. Discovery, synthesis, and characterization of an orally bioavailable, brain penetrant inhibitor of mixed lineage kinase 3. J Med Chem. 2013 Oct 24;56(20):8032-48. 2. Rhoo KH, et al. Pharmacologic inhibition of MLK3 kinase activity blocks the in vitro migratory capacity of breast cancer cells but has no effect on breast cancer brain metastasis in a mouse xenograft model. PLoS One. 2014 Sep 29;9(9):e108487.

• 溶解性： soluble  in  DMSO

• 保存条件： -20℃

• 配置溶液浓度参考：
  

  	1mg	5mg	10mg
  1 mM	2.372 ml	11.861 ml	23.723 ml
  5 mM	0.474 ml	2.372 ml	4.745 ml
  10 mM	0.237 ml	1.186 ml	2.372 ml
  50 mM	0.047 ml	0.237 ml	0.474 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 分子摩尔量 (g/mol)

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