| 產(chǎn)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. |
| 靶點： |
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 |
| 體外研究： |
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。 |
| 體內(nèi)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。 |
| 參考文獻： |
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 |
| 保存條件： |
-20℃ |
| 配置溶液濃度參考： |
|
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 |
|
| 注意： |
部分產(chǎn)品我司僅能提供部分信息，我司不保證所提供信息的權威性，僅供客戶參考交流研究之用。 |
上海工商
危險品化學品經(jīng)營許可證（不帶存儲）
營業(yè)執(zhí)照(三證合一)
北京