WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 510257
CAS#: 1351761-44-8 (free base)
Description: GNE-7915 is a potent LRRK2 kinase inhibitor, which possess an ideal balance of LRRK2 cellular potency, broad kinase selectivity, metabolic stability, and brain penetration across multiple species. GNE-7915 was reported as a potent (IC50=9 nM) selective (1/187 kinases), brain-penetrant and non-toxic inhibitor of LRRK2.
MedKoo Cat#: 510257
Name: GNE-7915
CAS#: 1351761-44-8 (free base)
Chemical Formula: C19H21F4N5O3
Exact Mass: 443.15805
Molecular Weight: 443.39535
Elemental Analysis: C, 51.47; H, 4.77; F, 17.14; N, 15.79; O, 10.83
Related CAS #: 2070015-00-6 (tosylate) 1351761-44-8 (free base)
Synonym: GNE7915; GNE 7915; GNE-7915.
IUPAC/Chemical Name: (4-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone
InChi Key: XCFLWTZSJYBCPF-UHFFFAOYSA-N
InChi Code: InChI=1S/C19H21F4N5O3/c1-3-24-16-12(19(21,22)23)10-25-18(27-16)26-14-9-13(20)11(8-15(14)30-2)17(29)28-4-6-31-7-5-28/h8-10H,3-7H2,1-2H3,(H2,24,25,26,27)
SMILES Code: O=C(C1=CC(OC)=C(NC2=NC=C(C(F)(F)F)C(NCC)=N2)C=C1F)N3CCOCC3
Appearance: 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
| Biological target: | GNE-7915 is an inhibitor of LRRK2 with an IC50 of 9 nM. |
| In vitro activity: | Whether LRRK2 G2019S-induced mtDNA damage is kinase dependent was investigated. A pretreatment paradigm in which primary midbrain neuronal cultures were treated with vehicle or GNE-7915 for 24 h and then transduced with either GFP or LRRK2 G2019S for 24 h was used. Pretreatment with GNE-7915 was able to prevent LRRK2 G2019S-induced mtDNA damage (Fig. 4A). Mitochondrial DNA copy number was unaffected by treatments (Fig. 4B). Importantly, treatment of GNE-7915 by itself did not alter mtDNA damage levels or copy number (Supplementary Material, Fig. S2). It was also confirmed that treatment with GNE-7915 reduced levels of LRRK2 pSer935, as these sites may be modulated indirectly by LRRK2 kinase activity and dephosphorylation occurs with LRRK2 kinase inhibitor exposure (Supplementary Material, Fig. S3). Reference: Hum Mol Genet. 2017 Nov 15;26(22):4340-4351. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886254/ |
| In vivo activity: | The effects of LRRK2 inhibitor GNE-7915 on R1441G Tg mice were examined to see whether GNE-7915 could alleviate DA (dopamine) transmission deficits. When treated with 1 μM GNE-7915 for 2 h, a significant increase of PPR (pair-pulse ratio) was observed (PPR/5s, control: 0.45 ± 0.01, treated: 0.48 ± 0.01, n = 10, P < 0.05; PPR/10s, control: 0.61 ± 0.005, treated: 0.66 ± 0.008, n = 10, P < 0.01; PPR/20s, control: 0.80 ± 0.015, treated: 0.84 ± 0.002, n = 10, P < 0.001, Figure 6). Single-pulse-evoked DA release was also enhanced (control: 1.93 ± 0.15 μM, n = 10; treated: 2.17 ± 0.19 μM, n = 10, P < 0.05, Figure 6). Reference: CNS Neurosci Ther. 2017 Feb;23(2):162-173. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5248597/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 10.0 | 22.55 | |
| Ethanol | 1.0 | 2.25 |
The following data is based on the product molecular weight 443.39535 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.
| 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. Howlett EH, Jensen N, Belmonte F, Zafar F, Hu X, Kluss J, Schüle B, Kaufman BA, Greenamyre JT, Sanders LH. LRRK2 G2019S-induced mitochondrial DNA damage is LRRK2 kinase dependent and inhibition restores mtDNA integrity in Parkinson's disease. Hum Mol Genet. 2017 Nov 15;26(22):4340-4351. doi: 10.1093/hmg/ddx320. PMID: 28973664; PMCID: PMC5886254. 2. Qin Q, Zhi LT, Li XT, Yue ZY, Li GZ, Zhang H. Effects of LRRK2 Inhibitors on Nigrostriatal Dopaminergic Neurotransmission. CNS Neurosci Ther. 2017 Feb;23(2):162-173. doi: 10.1111/cns.12660. Epub 2016 Dec 9. PMID: 27943591; PMCID: PMC5248597. |
| In vitro protocol: | 1. Howlett EH, Jensen N, Belmonte F, Zafar F, Hu X, Kluss J, Schüle B, Kaufman BA, Greenamyre JT, Sanders LH. LRRK2 G2019S-induced mitochondrial DNA damage is LRRK2 kinase dependent and inhibition restores mtDNA integrity in Parkinson's disease. Hum Mol Genet. 2017 Nov 15;26(22):4340-4351. doi: 10.1093/hmg/ddx320. PMID: 28973664; PMCID: PMC5886254. |
| In vivo protocol: | 1. Qin Q, Zhi LT, Li XT, Yue ZY, Li GZ, Zhang H. Effects of LRRK2 Inhibitors on Nigrostriatal Dopaminergic Neurotransmission. CNS Neurosci Ther. 2017 Feb;23(2):162-173. doi: 10.1111/cns.12660. Epub 2016 Dec 9. PMID: 27943591; PMCID: PMC5248597. |
1: Baptista MAS, Merchant K, Barrett T, Bhargava S, Bryce DK, Ellis JM, Estrada AA, Fell MJ, Fiske BK, Fuji RN, Galatsis P, Henry AG, Hill S, Hirst W, Houle C, Kennedy ME, Liu X, Maddess ML, Markgraf C, Mei H, Meier WA, Needle E, Ploch S, Royer C, Rudolph K, Sharma AK, Stepan A, Steyn S, Trost C, Yin Z, Yu H, Wang X, Sherer TB. LRRK2 inhibitors induce reversible changes in nonhuman primate lungs without measurable pulmonary deficits. Sci Transl Med. 2020 Apr 22;12(540):eaav0820. doi: 10.1126/scitranslmed.aav0820. PMID: 32321864.
2: Liu H, Ho PW, Leung CT, Pang SY, Chang EES, Choi ZY, Kung MH, Ramsden DB, Ho SL. Aberrant mitochondrial morphology and function associated with impaired mitophagy and DNM1L-MAPK/ERK signaling are found in aged mutant Parkinsonian LRRK2R1441G mice. Autophagy. 2020 Dec 10:1-25. doi: 10.1080/15548627.2020.1850008. Epub ahead of print. PMID: 33300446.
3: Cao J, Zhuang Y, Zhang J, Zhang Z, Yuan S, Zhang P, Li H, Li X, Shen H, Wang Z, Chen G. Leucine-rich repeat kinase 2 aggravates secondary brain injury induced by intracerebral hemorrhage in rats by regulating the P38 MAPK/Drosha pathway. Neurobiol Dis. 2018 Nov;119:53-64. doi: 10.1016/j.nbd.2018.07.024. Epub 2018 Jul 23. PMID: 30048803.
4: Qin Q, Zhi LT, Li XT, Yue ZY, Li GZ, Zhang H. Effects of LRRK2 Inhibitors on Nigrostriatal Dopaminergic Neurotransmission. CNS Neurosci Ther. 2017 Feb;23(2):162-173. doi: 10.1111/cns.12660. Epub 2016 Dec 9. PMID: 27943591; PMCID: PMC5248597.
5: Kavanagh ME, Doddareddy MR, Kassiou M. The development of CNS-active LRRK2 inhibitors using property-directed optimisation. Bioorg Med Chem Lett. 2013 Jul 1;23(13):3690-6. doi: 10.1016/j.bmcl.2013.04.086. Epub 2013 May 9. PMID: 23721803.
6: Howlett EH, Jensen N, Belmonte F, Zafar F, Hu X, Kluss J, Schüle B, Kaufman BA, Greenamyre JT, Sanders LH. LRRK2 G2019S-induced mitochondrial DNA damage is LRRK2 kinase dependent and inhibition restores mtDNA integrity in Parkinson's disease. Hum Mol Genet. 2017 Nov 15;26(22):4340-4351. doi: 10.1093/hmg/ddx320. PMID: 28973664; PMCID: PMC5886254.
7: Estrada AA, Liu X, Baker-Glenn C, Beresford A, Burdick DJ, Chambers M, Chan BK, Chen H, Ding X, DiPasquale AG, Dominguez SL, Dotson J, Drummond J, Flagella M, Flynn S, Fuji R, Gill A, Gunzner-Toste J, Harris SF, Heffron TP, Kleinheinz T, Lee DW, Le Pichon CE, Lyssikatos JP, Medhurst AD, Moffat JG, Mukund S, Nash K, Scearce-Levie K, Sheng Z, Shore DG, Tran T, Trivedi N, Wang S, Zhang S, Zhang X, Zhao G, Zhu H, Sweeney ZK. Discovery of highly potent, selective, and brain- penetrable leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors. J Med Chem. 2012 Nov 26;55(22):9416-33. doi: 10.1021/jm301020q. Epub 2012 Oct 15. PMID: 22985112.
Mutations in PARK8/LRRK2 are the most common genetic cause of Parkinson's disease. Inhibition of LRRK2 kinase activity has neuroprotective benefits, and provides a means of addressing the underlying biochemical cause of Parkinson's disease for the first time. Initial attempts to develop LRRK2 inhibitors were largely unsuccessful and highlight shortcomings intrinsic to traditional, high throughput screening methods of lead discovery.
