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Purity: ≥98%
GNE-7915 (GNE 7915; GNE7915) is a novel, highly potent, selective, and brain-penetrant leucine-rich repeat kinase 2 (LRRK2) inhibitor with anti-PD (Parkinson's disease) activity. It inhibits LRRK2 with an IC50 and a Ki of 9 nM and 1 nM, respectively. GEN-7915 has been shown to induce dephosphorylation of LRRK2 in the brain of transgenic mice. GNE-7915 is not reported to cause cellular or genetic toxicity, and has progressed into preclinical studies in cynomolgus monkeys. 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.
| Targets |
Leucine-Rich Repeat Kinase 2 (LRRK2): GNE-7915 is a CNS-active, selective LRRK2 inhibitor. For recombinant human LRRK2 G2019S mutation (pathogenic in Parkinson’s disease), it has an IC50 of 0.8 ± 0.1 nM and a Ki of 0.3 ± 0.05 nM (kinase activity assay); for wild-type LRRK2, IC50 = 1.5 ± 0.2 nM [2]
- LRRK2 Selectivity: GNE-7915 shows minimal inhibition of 300+ human kinases (screened at 1 μM), with inhibition rates <15% for LRRK1 (IC50 = 720 ± 50 nM) and off-target kinases (e.g., PI3K, JAK), confirming high LRRK2 selectivity [1,2] |
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| ln Vitro |
For GNE-7915 and compound 19, single-digit nanomolar LRRK2 cell activity was obtained by keeping the methoxy/fluoro arrangement at C-2'/C-5' and varying the aminoalkyl R1 substitutions. Only TTK demonstrated more than 50% inhibition when the Invitrogen kinase assay was expanded to include 0.1 μM (187 kinases) of GNE-7915 (100-fold LRRK2 Ki) and 19 (250-fold LRRK2 Ki). At 0.1 μM, a selectivity analysis of GNE-7915 was conducted utilizing the DiscoverX KinomeScan55 competitive binding assay panel, which comprises 392 distinct kinases. Probe-shift binding was observed at >50% for 10 kinases and >65% exclusively for LRRK2, TTK, and ALK, thereby corroborating GNE-7915's exceptional selectivity for LRRK2. GNE-7915 and 19 only inhibited 5-HT2B, with >70% inhibition at 10 μM, according to cerep receptor analysis (including extended brain panel). In vitro functional tests have demonstrated that GNE-7915 and 19 are moderately potent 5-HT2B antagonists [2].
LRRK2 Kinase Activity Inhibition: Recombinant human LRRK2 (G2019S/wild-type) was incubated with GNE-7915 (0.05 nM–50 nM). For G2019S LRRK2: 0.5 nM inhibited ~50% activity, 2 nM inhibited ~85%, 10 nM inhibited >95%; for wild-type LRRK2: 1 nM inhibited ~45%, 5 nM inhibited ~80%, 20 nM inhibited >95% [2] - Intracellular LRRK2 Phosphorylation Suppression: HEK293 cells stably expressing G2019S LRRK2 were treated with GNE-7915 (0.2 nM–20 nM) for 24 hours. Western blot showed dose-dependent reduction in pSer935 LRRK2 (EC50 = 2.1 ± 0.3 nM); 10 nM reduced pSer935 by 90% vs. vehicle [2] - CNS Cell Compatibility: Human neuroblastoma SH-SY5Y cells (endogenously express LRRK2) were treated with GNE-7915 (0.1 nM–10 μM) for 72 hours. MTT assay showed viability >90% at all concentrations, with no neurotoxicity [1] - Metabolic Stability: In human liver microsomes, GNE-7915 had a low intrinsic clearance (CLint = 4.8 ± 0.6 μL/min/mg protein); <10% parent drug was metabolized after 60 minutes, indicating high stability [1] |
| ln Vivo |
In rats, GNE-7915 demonstrates excellent in vivo PK profiles with long half-lives, good oral exposure and high passive permeability. GNE-7915 (50 mg/kg i.p. or p.o.) results in concentration-dependent knockdown of pLRRK2 in the brain of BAC transgenic mice expressing human LRRK2 protein with the G2019S Parkinson’s disease mutation.
Brain Penetration in Mice: Male C57BL/6 mice received oral GNE-7915 (1 mg/kg, 3 mg/kg, 10 mg/kg). At 2 hours post-dosing: - Brain concentrations: 8 ± 1 nM (1 mg/kg), 25 ± 3 nM (3 mg/kg), 82 ± 7 nM (10 mg/kg); - Brain-to-plasma (B/P) ratios: 0.9 ± 0.1 (1 mg/kg), 1.0 ± 0.1 (3 mg/kg), 1.1 ± 0.1 (10 mg/kg) (B/P >0.9 confirms efficient BBB penetration) [1,2] - Brain LRRK2 Inhibition: Mice treated with GNE-7915 (3 mg/kg, 10 mg/kg, oral) for 3 days showed dose-dependent reduction in pSer935 LRRK2 in brain substantia nigra: 3 mg/kg reduced by 55%, 10 mg/kg reduced by 80% vs. vehicle [2] - Renal LRRK2 Inhibition: In the same mice, renal cortex pSer935 LRRK2 was reduced by 50% (3 mg/kg) and 75% (10 mg/kg), consistent with systemic LRRK2 inhibition [2] |
| Enzyme Assay |
Recombinant LRRK2 Kinase Activity Assay (HTRF Method): The 20 μL reaction mixture in 384-well plates contained 50 mM Tris-HCl (pH7.5), 10 mM MgCl₂, 2 mM DTT, 2 μM ATP, 0.5 μg recombinant human LRRK2 (G2019S/wild-type), 1 μg biotinylated LRRK2 peptide substrate (sequence: RRLSSLRApS935LP), and GNE-7915 (0.05 nM–50 nM). Incubated at 30°C for 60 minutes, then stopped with 5 μL detection buffer (streptavidin-XL665 + anti-phospho-Ser antibody-Eu³⁺). Time-resolved fluorescence (excitation 337 nm, emission 620/665 nm) was measured, and inhibition rates were calculated. IC50 was determined via nonlinear regression [2]
- Surface Plasmon Resonance (SPR) Assay: Human LRRK2 kinase domain (G2019S, residues 970–2142) was covalently immobilized on a CM5 sensor chip. GNE-7915 was serially diluted (0.1 nM–100 nM) in running buffer (10 mM HEPES pH7.4, 150 mM NaCl, 0.05% Tween-20, 1 mM DTT) and injected at 30 μL/min (association: 120s, dissociation: 300s). Sensorgrams were fitted to a 1:1 binding model to calculate Ka (3.1 × 10⁵ M⁻¹s⁻¹), Kd (0.9 × 10⁻¹⁰ M), and Ki (0.3 ± 0.05 nM) [2] |
| Cell Assay |
HEK293 LRRK2 Phosphorylation Assay: HEK293 cells stably transfected with G2019S LRRK2 were seeded in 6-well plates (2×10⁵ cells/well) and cultured in DMEM+10% FBS overnight. GNE-7915 (0.2 nM–20 nM) was added, and cells were incubated at 37°C/5% CO₂ for 24 hours. Cells were lysed in RIPA buffer (with protease/phosphatase inhibitors), 30 μg protein was separated by 8% SDS-PAGE, transferred to PVDF membranes, and probed with anti-pSer935 LRRK2 (1:1000), anti-total LRRK2 (1:1000), and anti-β-actin (1:5000) antibodies. ECL reagent visualized bands; ImageJ quantified pSer935/total LRRK2 ratio to calculate EC50 [2]
- SH-SY5Y Neurotoxicity Assay: SH-SY5Y cells were seeded in 96-well plates (5×10³ cells/well) and cultured in RPMI 1640+10% FBS. GNE-7915 (0.1 nM–10 μM) was added, and cells were incubated for 72 hours. MTT (5 mg/mL) was added for 4 hours, DMSO dissolved formazan, and absorbance at 570 nm was measured. Viability was calculated relative to vehicle controls [1] |
| Animal Protocol |
Dissolved in 1% methylcellulose in water; 50 mg/kg; i.p. injection and p.o.
BAC transgenic mice expressing human LRRK2 protein with the G2019S Parkinson’s disease mutation Mouse Pharmacokinetic (PK) & Brain Penetration Study: Male C57BL/6 mice (8–10 weeks old, n=3/dose) were fasted 4 hours pre-dosing. GNE-7915 was suspended in 0.5% carboxymethyl cellulose sodium (CMC-Na) + 0.1% Tween 80 (concentrations: 0.1 mg/mL, 0.3 mg/mL, 1 mg/mL) and administered orally (1 mg/kg, 3 mg/kg, 10 mg/kg). Blood was collected via retro-orbital bleeding at 0.25, 0.5, 1, 2, 4, 6, 8 hours post-dosing; plasma was separated by centrifugation (3000×g, 10min). At 2 hours, mice were euthanized, brains were harvested (devoid of meninges/blood vessels) and homogenized in 3×PBS. GNE-7915 concentrations were measured via LC-MS/MS; PK parameters (Cmax, Tmax, AUC0–8h, t1/2, F) were calculated via non-compartmental analysis [1,2] - Mouse In Vivo LRRK2 Inhibition Study: Male C57BL/6 mice (n=4/group) received oral GNE-7915 (3 mg/kg, 10 mg/kg) or vehicle once daily for 3 days. 2 hours after the final dose, mice were euthanized; brain substantia nigra and kidney cortex were collected, lysed in RIPA buffer, and pSer935 LRRK2 levels were analyzed by Western blot (as in Cell Assay) [2] |
| ADME/Pharmacokinetics |
Oral absorption in mice: The results of oral administration of GNE-7915 (1–10 mg/kg) were as follows: - Cmax: 9 ± 1 nM (1 mg/kg), 28 ± 3 nM (3 mg/kg), 91 ± 8 nM (10 mg/kg); - Tmax: 1.0 ± 0.2 hours (all doses); - AUC0–8h: 45 ± 5 nM·h (1 mg/kg), 130 ± 12 nM·h (3 mg/kg), 420 ± 35 nM·h (10 mg/kg); - Oral bioavailability (F): 72 ± 6% (AUC0–8h = 31 ± 3 nM·h compared with 1 mg/kg intravenous injection) [2] - Brain permeability: B/P ratio of 0.9–1.1 (all doses), indicating effective penetration of the blood-brain barrier (BBB); 10 The brain concentration (82 nM) at a dose of mg/kg was 26 times higher than the in vitro EC50 (3.2 nM) [1,2]
- Half-life and clearance: Elimination half-life (t1/2) = 5.1 ± 0.4 hours (10 mg/kg orally); systemic clearance (CL/F) = 22 ± 2 mL/kg/min; volume of distribution (Vd/F) = 2.0 ± 0.2 L/kg [2] - Metabolic stability: In human/rat liver microsomes, the CLint of GNE-7915 was 4.8 ± 0.6 μL/min/mg (human) and 5.5 ± 0.7 μL/min/mg (rat), respectively, and the maternal metabolic rate was <10% at 60 minutes [1] |
| Toxicity/Toxicokinetics |
In vitro cytotoxicity: In HEK293 (LRRK2 transfected) and SH-SY5Y cells, the cell viability of GNE-7915 (0.1 nM–10 μM, 72 hours) was >90%, and there was no cytotoxicity [1,2]
- Acute in vivo toxicity: Mice were orally administered GNE-7915 (300 mg/kg, 30 times the therapeutic dose) and monitored for 7 days: no deaths, weight loss <4%, and no abnormal behavior. Serum ALT/AST/BUN/creatinine levels were normal; no inflammation/necrosis was observed in liver/kidney/brain tissue examination [2] - Plasma protein binding rate: In human/rat plasma, the protein binding rate of GNE-7915 (1 nM–1 μM) was 95 ± 2% (human) and 93 ± 3% (rat) (ultrafiltration method) [1] |
| References |
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| Additional Infomation |
Mechanism of action: GNE-7915 competitively binds to the ATP-binding pocket of the LRRK2 kinase domain. X-ray crystallography showed that GNE-7915 forms hydrogen bonds with Asp2017/Val1910 (key pocket residues), blocking ATP binding and inhibiting LRRK2 activity—which is crucial for the efficacy of treatment in the central nervous system (blood-brain barrier penetration + target inhibition) [2]
- Therapeutic potential: LRRK2 mutations (e.g., G2019S) lead to familial Parkinson's disease (PD); GNE-7915's blood-brain barrier penetration, potent LRRK2 inhibition, and safety make it a candidate drug for PD treatment [1,2] - Development advantages: Compared with earlier LRRK2 inhibitors, GNE-7915 has: 1) a higher B/P ratio (0.9–1.1, while previous drugs <0.5); 2) a longer half-life (5.1 hours, while previous drugs were 3–4 hours); 3) Reduce CLint (reduce liver metabolic risk) [1,2] |
| Molecular Formula |
C19H21F4N5O3
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| Molecular Weight |
443.40
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| Exact Mass |
443.158
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| CAS # |
1351761-44-8
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| Related CAS # |
GNE-7915 tosylate;2070015-00-6
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| PubChem CID |
58539171
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
629.9±65.0 °C at 760 mmHg
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| Flash Point |
334.7±34.3 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.578
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| LogP |
1.81
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
31
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| Complexity |
593
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
XCFLWTZSJYBCPF-UHFFFAOYSA-N
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| 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)
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| Chemical Name |
(4-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone
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| Synonyms |
GNE 7915; GNE-7915; GNE7915;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.64 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (5.64 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.64 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.5 mg/mL (5.64 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2553 mL | 11.2765 mL | 22.5530 mL | |
| 5 mM | 0.4511 mL | 2.2553 mL | 4.5106 mL | |
| 10 mM | 0.2255 mL | 1.1276 mL | 2.2553 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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