URMC-099

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

URMC-099 是一种有效的、口服生物可利用的、混合谱系激酶 3 (MLK3) 的脑渗透抑制剂，IC50 为 14 nM。

URMC-099 is a potent, orally bioavailable, brain penetrant inhibitor of mixed lineage kinase 3 (MLK3) with IC50 of 14 nM; shows >90% inhibition against 111 kinases in a panel of 442 kinases at 1 uM; URMC-099 likely functions in HIV-1 associated neurocognitive disorders (HAND) preclinical models by inhibiting multiple kinase pathways, including MLK3 and LRRK2 (IC50=11 nM); inhibits LPS-induced TNFα release in microglial cells, HIV-1 Tat-induced release of cytokines in human monocytes and up-regulation of phospho-JNK in Tat-injected brains of mice.

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.

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)). 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.

URMC099

MAPK/ERK Signaling

MLK

Abl1|AuroraA|AuroraB|AuroraC|CDK1|CDK2|c-Met|DLK|IGF-1R|InsulinReceptor|Lck|LRRK2|MEKK2|MLK1|MLK2|MLK3|ROCK1|ROCK2|SGK|SGK1|Syk|TrkA|TrkB|VEGFR1/FLT1

Neurological Disease

——

1229582-33-5

421.5368

C27H27N5

>98% (HPLC)

DMSO: ≥ 33 mg/mL

CN1CCN(CC2=CC=C(C3=CN=C(NC=C4C5=CC6=C(NC=C6)C=C5)C4=C3)C=C2)CC1

1H-Pyrrolo[2,3-b]pyridine, 3-(1H-indol-5-yl)-5-[4-[(4-methyl-1-piperazinyl)methyl]phenyl]-

(-20℃)

With Ice Pack

≥ 2 years