| Identification | Back Directory | [Name]
URMC-099 | [CAS]
1229582-33-5 | [Synonyms]
RMC099
CS-1776
URMC-099
URMC-099;URMC 099
3-(1H-indol-5-yl)-5-[4-[(4-methyl-1-piperazinyl)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridine
1H-?Pyrrolo[2,?3-?b]?pyridine, 3-?(1H-?indol-?5-?yl)?-?5-?[4-?[(4-?methyl-?1-?piperazinyl)?methyl]?phenyl]?-
3-(1H-indol-5-yl)-5-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridine URMC-099 | [Molecular Formula]
C27H27N5 | [MDL Number]
MFCD28168077 | [MOL File]
1229582-33-5.mol | [Molecular Weight]
421.54 |
| Chemical Properties | Back Directory | [density ]
1.256±0.06 g/cm3(Predicted) | [storage temp. ]
-20°C | [solubility ]
Soluble in DMSO (>25 mg/ml) | [form ]
solid | [pka]
13.49±0.40(Predicted) | [color ]
Off-white | [Stability:]
Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months. | [InChIKey]
QKKIWEILHCXECO-UHFFFAOYSA-N | [SMILES]
C12NC=C(C3C=CC4=C(C=3)C=CN4)C1=CC(C1=CC=C(CN3CCN(C)CC3)C=C1)=CN=2 |
| Hazard Information | Back Directory | [Description]
URMC-099 (1229582-33-5) is a potent (IC50 = 14 nM), brain penetrant mixed-lineage kinase 3 inhibitor (MLK3). It also potently inhibits FLT3 (4 nM in vitro, but 560 nM in vivo), LRRK2 (11 nM), and ABL1 (3 nM).1 URMC-099 displayed neuroprotective effects in HIV-associated neurocognitive disorders2 and facilitated microglial amyloid-β degradation and clearance in mouse models.3,4 URMC-099 increased CD8+ T cells in mice and increased the CD8+GZMB+ T cell population in blood mononuclear cells isolated from breast cancer patients.5 | [Uses]
URMC-099 is an orally bioavailable MLK3 inhibitor used in the treatment of Parkinson’s disease and HIV-1 associated neurocognitive disorders. | [in vivo]
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[2]. | [IC 50]
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 nM (IC50); ZAP70: 5050 nM (IC50); ERK2: 6290 nM (IC50); P38α: 12050 nM (IC50); CYP3A4: 16.2 μM (IC50) | [References]
1) Goodfellow et al. (2013), Discovery, synthesis, and characterization of an orally bioavailable, brain penetrant inhibitor of mixed lineage kinase 3; J. Med. Chem. 56 8032
2) Marker et al. (2013), The new small-molecule mixed-lineage kinase 3 inhibitor URMC-099 is neuroprotective and anti-inflammatory in models of human immunodeficiency virus-associated neurocognitive disorders; J. Neurosc. 33 9998
3) Dong et al. (2016), The mixed-lineage kinase 3 inhibitor URMC-099 facilitates microglial amyloid-β degradation; J. Neuroinflammation 13 184
4) Kiyota et al. (2018), URMC-099 facilitates amyloid-β clearance in a murine model of Alzheimer’s disease; J. Neuroinflammation 15 137
5) Kumar et al. (2020), Mixed lineage kinase 3 inhibition induces T cell activation and cytotoxicity; Proc. Natl. Acad. Sci. USA 9 34567 |
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