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MedKoo Cat#: 510349 | Name: URMC-099
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

URMC-099 is an orally bioavailable, brain penetrant mixed lineage kinase (MLK) inhibitor with IC50 of 19 nM, 42 nM, 14 nM, and 150 nM, for MLK1, MLK2, MLK3, and DLK, respectively. MLK3 activation is associated with many of the pathologic hallmarks of HAND and therefore represents a prime target for adjunctive therapy based on small-molecule kinase inhibition. In vitro, URMC-099 treatment reduced inflammatory cytokine production by HIV-1 Tat-exposed microglia and prevented destruction and phagocytosis of cultured neuronal axons by these cells.

Chemical Structure

URMC-099
URMC-099
CAS#1229582-33-5

Theoretical Analysis

MedKoo Cat#: 510349

Name: URMC-099

CAS#: 1229582-33-5

Chemical Formula: C27H27N5

Exact Mass: 421.2267

Molecular Weight: 421.55

Elemental Analysis: C, 76.93; H, 6.46; N, 16.61

Price and Availability

Size Price Availability Quantity
10mg USD 90.00 Ready to ship
25mg USD 150.00 Ready to ship
50mg USD 250.00 Ready to ship
100mg USD 450.00 Ready to ship
200mg USD 750.00 Ready to ship
500mg USD 1,650.00 Ready to ship
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Related CAS #
No Data
Synonym
URMC099, URMC 099, URMC-099
IUPAC/Chemical Name
3-(1H-indol-5-yl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridine
InChi Key
QKKIWEILHCXECO-UHFFFAOYSA-N
InChi Code
InChI=1S/C27H27N5/c1-31-10-12-32(13-11-31)18-19-2-4-20(5-3-19)23-15-24-25(17-30-27(24)29-16-23)21-6-7-26-22(14-21)8-9-28-26/h2-9,14-17,28H,10-13,18H2,1H3,(H,29,30)
SMILES Code
CN1CCN(CC2=CC=C(C3=CN=C(NC=C4C5=CC6=C(NC=C6)C=C5)C4=C3)C=C2)CC1
Appearance
White to off-white solid powder
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not in water
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
Biological target:
URMC-099 is an orally bioavailable and potent mixed lineage kinase type 3 (MLK3) (IC50=14 nM) inhibitor with excellent blood-brain barrier penetration properties.
In vitro activity:
URMC-099 (300 nM) blocked increases in JUN ( expression as well as phosphorylation at serine residues 63 and 73 (Fig. 3C,D; n = 3 cultures per condition, p = 0.015 for P Ser 73 JUN in 099- vs vehicle-treated cultures at 8 h and p = 0.003 at 12 h, one-way ANOVA with Sidak post hoc testw,x), consistent with reduced JNK (c-Jun N-terminal kinase) activity downstream of MLK inhibition. Treatment with CLFB1134 (a highly-specific MLK3 inhibitor with a different chemical scaffold) failed to provide protection or trophic support to NGF (nerve growth factor)-deprived neurons, which underwent neuritic beading and degeneration of cell bodies to an extent that precluded quantification of pyknotic versus healthy nuclei, suggesting that the neuroprotective effects of broad-spectrum MLK inhibition in vitro, like in vivo, are not reproduced by an inhibitor that is highly selective for MLK3. Thus, subsequent experiments focused on further characterizing the effects of URMC-099 in EAE (autoimmune encephalomyelitis) hippocampus. Reference: eNeuro. 2018 Nov-Dec; 5(6): ENEURO.0245-18.2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325567/
In vivo activity:
At 24 h post-surgery, hippocampal microgliosis was observed in vehicle-treated mice receiving orthopedic surgery relative to sham-treated controls using stereological analyses of F4/80+ cells (P = 0.0003; Fig. 1a, b). In contrast, URMC-099-treated mice exhibited a significant reduction (P = 0.0003) in the density of F4/80+ cells in the hippocampus relative to the sham-treated controls (Fig. 1b), indicating that our treatment paradigm effectively inhibited surgery-induced hippocampal microgliosis. BBB integrity was examined also using IgG immunostaining. There was significantly less IgG leakage in URMC-099-treated mice receiving surgery and sham-treated controls when compared to vehicle-treated mice receiving surgery (P values ≤ 0.044; Fig. 1c). Hence, URMC-099 was efficacious in preventing both microgliosis and leakage at the BBB. Reference: J Neuroinflammation. 2019; 16: 193. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816182/
Solvent mg/mL mM
Solubility
DMSO 29.0 68.79
DMF 25.0 59.30
DMF:PBS (pH 7.2) (1:1) 0.5 1.19
Ethanol 1.0 2.37
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 421.55 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol:
1. Bellizzi MJ, Hammond JW, Li H, Gantz Marker MA, Marker DF, Freeman RS, Gelbard HA. The Mixed-Lineage Kinase Inhibitor URMC-099 Protects Hippocampal Synapses in Experimental Autoimmune Encephalomyelitis. eNeuro. 2018 Dec 3;5(6):ENEURO.0245-18.2018. doi: 10.1523/ENEURO.0245-18.2018. PMID: 30627663; PMCID: PMC6325567. 2. Saminathan P, Kevadiya BD, Marker DF, Gendelman HE, Gorantla S, Gelbard HA. Broad Spectrum Mixed Lineage Kinase Type 3 Inhibition and HIV-1 Persistence in Macrophages. J Neuroimmune Pharmacol. 2019 Mar;14(1):44-51. doi: 10.1007/s11481-018-09829-8. Epub 2019 Jan 7. PMID: 30617749; PMCID: PMC6391203. 3. Miller-Rhodes P, Kong C, Baht GS, Saminathan P, Rodriguiz RM, Wetsel WC, Gelbard HA, Terrando N. The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders. J Neuroinflammation. 2019 Oct 28;16(1):193. doi: 10.1186/s12974-019-1582-5. PMID: 31660984; PMCID: PMC6816182. 4. Calamaras TD, Baumgartner RA, Aronovitz MJ, McLaughlin AL, Tam K, Richards DA, Cooper CW, Li N, Baur WE, Qiao X, Wang GR, Davis RJ, Kapur NK, Karas RH, Blanton RM. Mixed lineage kinase-3 prevents cardiac dysfunction and structural remodeling with pressure overload. Am J Physiol Heart Circ Physiol. 2019 Jan 1;316(1):H145-H159. doi: 10.1152/ajpheart.00029.2018. Epub 2018 Oct 26. PMID: 30362822; PMCID: PMC6383356.
In vitro protocol:
1. Bellizzi MJ, Hammond JW, Li H, Gantz Marker MA, Marker DF, Freeman RS, Gelbard HA. The Mixed-Lineage Kinase Inhibitor URMC-099 Protects Hippocampal Synapses in Experimental Autoimmune Encephalomyelitis. eNeuro. 2018 Dec 3;5(6):ENEURO.0245-18.2018. doi: 10.1523/ENEURO.0245-18.2018. PMID: 30627663; PMCID: PMC6325567. 2. Saminathan P, Kevadiya BD, Marker DF, Gendelman HE, Gorantla S, Gelbard HA. Broad Spectrum Mixed Lineage Kinase Type 3 Inhibition and HIV-1 Persistence in Macrophages. J Neuroimmune Pharmacol. 2019 Mar;14(1):44-51. doi: 10.1007/s11481-018-09829-8. Epub 2019 Jan 7. PMID: 30617749; PMCID: PMC6391203.
In vivo protocol:
1. Miller-Rhodes P, Kong C, Baht GS, Saminathan P, Rodriguiz RM, Wetsel WC, Gelbard HA, Terrando N. The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders. J Neuroinflammation. 2019 Oct 28;16(1):193. doi: 10.1186/s12974-019-1582-5. PMID: 31660984; PMCID: PMC6816182. 2. Calamaras TD, Baumgartner RA, Aronovitz MJ, McLaughlin AL, Tam K, Richards DA, Cooper CW, Li N, Baur WE, Qiao X, Wang GR, Davis RJ, Kapur NK, Karas RH, Blanton RM. Mixed lineage kinase-3 prevents cardiac dysfunction and structural remodeling with pressure overload. Am J Physiol Heart Circ Physiol. 2019 Jan 1;316(1):H145-H159. doi: 10.1152/ajpheart.00029.2018. Epub 2018 Oct 26. PMID: 30362822; PMCID: PMC6383356.
1: Chiang W, Urban JM, Yanchik-Slade F, Stout A, Hammond JM, Nilsson BL, Gelbard HA, Krauss TD. Hybrid Amyloid Quantum Dot Nano-Bio Assemblies to Probe Neuroinflammatory Damage. ACS Chem Neurosci. 2024 Sep 4;15(17):3124-3135. doi: 10.1021/acschemneuro.4c00183. Epub 2024 Aug 15. PMID: 39146244; PMCID: PMC11378299. 2: Dos Santos M, Oliveira Costa AL, Vaz GHS, de Souza GCA, Vitor RWA, Martins- Duarte ÉS. Medicines for Malaria Venture Pandemic Box In Vitro Screening Identifies Compounds Highly Active against the Tachyzoite Stage of Toxoplasma gondii. Trop Med Infect Dis. 2023 Nov 29;8(12):510. doi: 10.3390/tropicalmed8120510. PMID: 38133442; PMCID: PMC10747034. 3: Chiang W, Stout A, Yanchik-Slade F, Li H, Terrando N, Nilsson BL, Gelbard HA, Krauss TD. Quantum Dot Biomimetic for SARS-CoV-2 to Interrogate Blood-Brain Barrier Damage Relevant to NeuroCOVID Brain Inflammation. ACS Appl Nano Mater. 2023 Aug 7;6(16):15094-15107. doi: 10.1021/acsanm.3c02719. PMID: 37649833; PMCID: PMC10463222. 4: Nair RS, Kumar S, Das S, Singh SK, Srivastava P, Sondarva G, Rao A, Sinha SC, Xiong R, Bloem L, Hoskins K, Thatcher GRJ, Rana B, Rana A. TrkA expression directs the anti-neoplastic activity of MLK3 inhibitors in triple-negative breast cancer. Oncogene. 2023 Mar;42(14):1132-1143. doi: 10.1038/s41388-023-02633-6. Epub 2023 Feb 22. PMID: 36813855. 5: Li M, Guo M, Xu Y, Wu L, Chen M, Dong Y, Zheng L, Chen D, Qiao Y, Ke Z, Shi X. Murine cytomegalovirus employs the mixed lineage kinases family to regulate the spiral ganglion neuron cell death and hearing loss. Neurosci Lett. 2023 Jan 10;793:136990. doi: 10.1016/j.neulet.2022.136990. Epub 2022 Nov 28. PMID: 36455693. 6: Ha AT, Cho JY, Kim D. MLK3 Regulates Inflammatory Response via Activation of AP-1 Pathway in HEK293 and RAW264.7 Cells. Int J Mol Sci. 2022 Sep 17;23(18):10874. doi: 10.3390/ijms231810874. PMID: 36142785; PMCID: PMC9501218. 7: Miller-Rhodes P, Li H, Velagapudi R, Chiang W, Terrando N, Gelbard HA. URMC-099 prophylaxis prevents hippocampal vascular vulnerability and synaptic damage in an orthopedic model of delirium superimposed on dementia. FASEB J. 2022 Jun;36(6):e22343. doi: 10.1096/fj.202200184RR. PMID: 35535564; PMCID: PMC9175136. 8: Calamaras TD, Pande S, Baumgartner RA, Kim SK, McCarthy JC, Martin GL, Tam K, McLaughlin AL, Wang GR, Aronovitz MJ, Lin W, Aguirre JI, Baca P, Liu P, Richards DA, Davis RJ, Karas RH, Jaffe IZ, Blanton RM. MLK3 mediates impact of PKG1α on cardiac function and controls blood pressure through separate mechanisms. JCI Insight. 2021 Sep 22;6(18):e149075. doi: 10.1172/jci.insight.149075. PMID: 34324442; PMCID: PMC8492323. 9: Zhao HF, Wu CP, Zhou XM, Diao PY, Xu YW, Liu J, Wang J, Huang XJ, Liu WL, Chen ZP, Huang GD, Li WP. Correction to: Synergism between the phosphatidylinositol 3-kinase p110β isoform inhibitor AZD6482 and the mixed lineage kinase 3 inhibitor URMC-099 on the blockade of glioblastoma cell motility and focal adhesion formation. Cancer Cell Int. 2021 Jul 28;21(1):403. doi: 10.1186/s12935-021-02028-1. Erratum for: Cancer Cell Int. 2021 Jan 6;21(1):24. doi: 10.1186/s12935-020-01728-4. PMID: 34321007; PMCID: PMC8320197. 10: Wang J, Deng B, Liu J, Liu Q, Guo Y, Yang Z, Fang C, Lu L, Chen Z, Xian S, Wang L, Huang Y. Xinyang Tablet inhibits MLK3-mediated pyroptosis to attenuate inflammation and cardiac dysfunction in pressure overload. J Ethnopharmacol. 2021 Jun 28;274:114078. doi: 10.1016/j.jep.2021.114078. Epub 2021 Mar 30. PMID: 33798659. 11: Tajbakhsh A, Read M, Barreto GE, Ávila-Rodriguez M, Gheibi-Hayat SM, Sahebkar A. Apoptotic neurons and amyloid-beta clearance by phagocytosis in Alzheimer's disease: Pathological mechanisms and therapeutic outlooks. Eur J Pharmacol. 2021 Mar 15;895:173873. doi: 10.1016/j.ejphar.2021.173873. Epub 2021 Jan 16. PMID: 33460611. 12: Zhao HF, Wu CP, Zhou XM, Diao PY, Xu YW, Liu J, Wang J, Huang XJ, Liu WL, Chen ZP, Huang GD, Li WP. Synergism between the phosphatidylinositol 3-kinase p110β isoform inhibitor AZD6482 and the mixed lineage kinase 3 inhibitor URMC-099 on the blockade of glioblastoma cell motility and focal adhesion formation. Cancer Cell Int. 2021 Jan 6;21(1):24. doi: 10.1186/s12935-020-01728-4. Erratum in: Cancer Cell Int. 2021 Jul 28;21(1):403. doi: 10.1186/s12935-021-02028-1. PMID: 33407478; PMCID: PMC7789614. 13: Kumar S, Singh SK, Viswakarma N, Sondarva G, Nair RS, Sethupathi P, Sinha SC, Emmadi R, Hoskins K, Danciu O, Thatcher GRJ, Rana B, Rana A. Mixed lineage kinase 3 inhibition induces T cell activation and cytotoxicity. Proc Natl Acad Sci U S A. 2020 Apr 7;117(14):7961-7970. doi: 10.1073/pnas.1921325117. Epub 2020 Mar 24. PMID: 32209667; PMCID: PMC7149389. 14: Bos PH, Lowry ER, Costa J, Thams S, Garcia-Diaz A, Zask A, Wichterle H, Stockwell BR. Development of MAP4 Kinase Inhibitors as Motor Neuron-Protecting Agents. Cell Chem Biol. 2019 Dec 19;26(12):1703-1715.e37. doi: 10.1016/j.chembiol.2019.10.005. Epub 2019 Oct 31. PMID: 31676236; PMCID: PMC7253076. 15: Miller-Rhodes P, Kong C, Baht GS, Saminathan P, Rodriguiz RM, Wetsel WC, Gelbard HA, Terrando N. The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders. J Neuroinflammation. 2019 Oct 28;16(1):193. doi: 10.1186/s12974-019-1582-5. PMID: 31660984; PMCID: PMC6816182. 16: Xu H, Cheng M, Chi X, Liu X, Zhou J, Lin T, Yang W. High-Throughput Screening Identifies Mixed-Lineage Kinase 3 as a Key Host Regulatory Factor in Zika Virus Infection. J Virol. 2019 Aug 28;93(18):e00758-19. doi: 10.1128/JVI.00758-19. PMID: 31270223; PMCID: PMC6714800. 17: Bellizzi MJ, Hammond JW, Li H, Gantz Marker MA, Marker DF, Freeman RS, Gelbard HA. The Mixed-Lineage Kinase Inhibitor URMC-099 Protects Hippocampal Synapses in Experimental Autoimmune Encephalomyelitis. eNeuro. 2018 Dec 3;5(6):ENEURO.0245-18.2018. doi: 10.1523/ENEURO.0245-18.2018. PMID: 30627663; PMCID: PMC6325567. 18: Saminathan P, Kevadiya BD, Marker DF, Gendelman HE, Gorantla S, Gelbard HA. Broad Spectrum Mixed Lineage Kinase Type 3 Inhibition and HIV-1 Persistence in Macrophages. J Neuroimmune Pharmacol. 2019 Mar;14(1):44-51. doi: 10.1007/s11481-018-09829-8. Epub 2019 Jan 7. PMID: 30617749; PMCID: PMC6391203. 19: Calamaras TD, Baumgartner RA, Aronovitz MJ, McLaughlin AL, Tam K, Richards DA, Cooper CW, Li N, Baur WE, Qiao X, Wang GR, Davis RJ, Kapur NK, Karas RH, Blanton RM. Mixed lineage kinase-3 prevents cardiac dysfunction and structural remodeling with pressure overload. Am J Physiol Heart Circ Physiol. 2019 Jan 1;316(1):H145-H159. doi: 10.1152/ajpheart.00029.2018. Epub 2018 Oct 26. PMID: 30362822; PMCID: PMC6383356. 20: Thomas MB, Gnanadhas DP, Dash PK, Machhi J, Lin Z, McMillan J, Edagwa B, Gelbard H, Gendelman HE, Gorantla S. Modulating cellular autophagy for controlled antiretroviral drug release. Nanomedicine (Lond). 2018 Sep;13(17):2139-2154. doi: 10.2217/nnm-2018-0224. Epub 2018 Aug 21. PMID: 30129397; PMCID: PMC6219451.