MLi-2
(Synonyms: REL-3-[6-[(2R,6S)-2,6-二甲基-4-吗啉基]-4-嘧啶基]-5-[(1-甲基环丙基)氧基]-1H-吲唑) 目录号 : GC30769
MLi-2是一种高效、选择性的富含亮氨酸重复激酶2（LRRK2）抑制剂，其IC₅₀值为0.76nM，MLi-2具有良好的中枢神经系统穿透能力，是研究LRRK2功能和帕金森病（PD）病理机制的重要工具化合物。
Cas No.:1627091-47-7
Sample solution is provided at 25 µL, 10mM.
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MLi-2 is a potent and selective inhibitor of leucine-rich repeat kinase 2 (LRRK2), with an IC₅₀ value of 0.76nM [1]. MLi-2 exhibits excellent central nervous system penetration and serves as an important tool compound for studying LRRK2 function and the pathological mechanisms of Parkinson’s disease (PD)[2-3]. Additionally, MLi-2 has been shown to alleviate DOPA-responsive dystonia[4].
In vitro, treatment with MLi-2 (100nM) for 2 hours in SH-SY5Y and MEF cells expressing either wild-type or 4xSA (S910A/S935A/S955A/S973A) mutant LRRK2 significantly inhibited LRRK2 kinase activity, as evidenced by a marked reduction in the phosphorylation levels of Rab8a (T72) and Rab10 (T73), as well as decreased autophosphorylation of LRRK2 at residues S910, S935, S955, and S973[5]. MLi-2 (1μM) treatment for 24 hours in primary microglia derived from wild-type and G2019S-LRRK2 mice significantly reduced LRRK2 phosphorylation at Ser935, indicating effective inhibition of LRRK2 kinase activity. RNA-Seq analysis revealed that MLi-2 treatment primarily upregulated genes associated with the regulation of ion transmembrane transport and downregulated genes involved in the positive regulation of apoptosis[6].
In vivo, MLi-2 (8 or 45mg/kg/day) was administered via diet to wild-type and LRRK2 G2019S knock-in mice injected with Alzheimer’s disease-derived tau fibrils. Treatment began one week prior to tau injection and continued for 6 months. MLi-2 significantly reduced tau pathology progression in cortical regions of G2019S mutant mice, with the effect being more pronounced at the 45mg/kg/day dose. MLi-2 also reversed the altered direction of pathology spread caused by the G2019S mutation. Additionally, long-term MLi-2 treatment led to enlargement of pneumocytes in the lungs[7]. MLi-2 (10mg/kg) was administered via intraperitoneal injection to 12-month-old LRRK2 G2019S knock-in (KI) mice to assess its effects on dopamine transporter (DAT) function. Although MLi-2 significantly inhibited LRRK2 kinase activity (as shown by a 75% reduction in pSer1292 LRRK2 levels), MLi-2 failed to reverse the abnormally elevated DAT uptake activity (Vmax) observed in G2019S KI mice[8].
References:
[1] Fell MJ, Mirescu C, Basu K, et al. MLi-2, a Potent, Selective, and Centrally Active Compound for Exploring the Therapeutic Potential and Safety of LRRK2 Kinase Inhibition. J Pharmacol Exp Ther. 2015 Dec;355(3):397-409.
[2] Hatcher JM, Zwirek M, Sarhan AR, et al. Development of a highly potent and selective degrader of LRRK2. Bioorg Med Chem Lett. 2023 Oct 1;94:129449.
[3] Tengberg JF, Russo F, Benned-Jensen T, et al. LRRK2 and RAB8A regulate cell death after lysosomal damage in macrophages through cholesterol-related pathways. Neurobiol Dis. 2024 Nov;202:106728.
[4] Roman KM, Dinasarapu AR, Cherian S, et al. Striatal cell-type-specific molecular signatures reveal potential therapeutic targets in a model of dystonia. Neurobiol Dis. 2025 Aug;212:106981.
[5] Kania E, Long JS, McEwan DG, et al. LRRK2 phosphorylation status and kinase activity regulate (macro)autophagy in a Rab8a/Rab10-dependent manner. Cell Death Dis. 2023 Jul 15;14(7):436.
[6] Nazish I, Mamais A, Mallach A, et al. Differential LRRK2 Signalling and Gene Expression in WT-LRRK2 and G2019S-LRRK2 Mouse Microglia Treated with Zymosan and MLi2. Cells. 2023 Dec 26;13(1):53.
[7] Lubben N, Brynildsen JK, Webb CM, et al. LRRK2 kinase inhibition reverses G2019S mutation-dependent effects on tau pathology progression. Transl Neurodegener. 2024 Mar 4;13(1):13.
[8] Domenicale C, Mercatelli D, Albanese F, et al. Dopamine Transporter, PhosphoSerine129 α-Synuclein and α-Synuclein Levels in Aged LRRK2 G2019S Knock-In and Knock-Out Mice. Biomedicines. 2022 Apr 12;10(4):881.
MLi-2是一种高效、选择性的富含亮氨酸重复激酶2（LRRK2）抑制剂，其IC₅₀值为0.76nM[1]，MLi-2具有良好的中枢神经系统穿透能力，是研究LRRK2功能和帕金森病（PD）病理机制的重要工具化合物[2-3]。此外，MLi-2还被证明具有缓解DOPA反应性肌张力障碍的功能[3-4]。
在体外，MLi-2（100nM）处理表达野生型或4xSA（S910A/S935A/S955A/S973A）突变型LRRK2的SH-SY5Y细胞和MEF细胞2小时，显著抑制了LRRK2激酶活性，表现为Rab8a（T72）和Rab10（T73）磷酸化水平显著下降，同时降低了LRRK2自身在S910/S935/S955/S973位点的磷酸化水平[5]。MLi-2（1μM）处理野生型和G2019S-LRRK2小鼠原代小胶质细胞24小时，显著抑制了LRRK2在Ser935位点的磷酸化水平，提示其有效抑制LRRK2激酶活性。RNA-Seq分析显示，MLi-2处理主要上调了与离子跨膜转运调控相关的基因表达，并下调了与细胞凋亡正向调控相关的基因[6]。
在体内，MLi-2（8或45mg/kg/天）通过饮食给药，用于处理注射了阿尔茨海默病来源tau纤维的野生型和LRRK2 G2019S敲入小鼠，给药时间为tau注射前1周开始，并持续6个月。MLi-2在G2019S突变小鼠中显著减少了皮质区域的tau病理进展，尤其在45mg/kg/天的剂量下效果更为明显，同时逆转了由G2019S突变引起的病理扩散方向改变。此外，长期给予MLi-2还导致小鼠肺泡细胞（pneumocytes）体积增大[7]。MLi-2（10mg/kg）通过腹腔注射给药，用于处理12月龄的LRRK2 G2019S敲入（KI）小鼠，以评估其对多巴胺转运体（DAT）功能的影响。尽管MLi-2显著抑制了LRRK2激酶活性（pSer1292 LRRK2水平下降75%），但未能逆转G2019S KI小鼠中异常升高的DAT摄取活性（Vmax）[8]。
| Cell experiment [1]: | |
Cell lines | Primary microglia from wild-type and LRRK2 G2019S knock-in mice |
Preparation Method | Primary microglia were isolated from postnatal day 1–2 mouse brains and cultured for approximately 10 days. Cells were then treated with zymosan (200µg/mL) and/or MLi-2(1µM) for 24 hours to assess inflammatory and transcriptional responses. |
Reaction Conditions | 1µM MLi-2; 24 hours |
Applications | MLi-2 significantly inhibited LRRK2 kinase activity, as shown by reduced phosphorylation at Ser935, and modulated gene expression profiles, particularly upregulating genes involved in ion transmembrane transport regulation and downregulating genes related to apoptotic processes in both wild-type and G2019S-LRRK2 microglia. |
| Animal experiment [2]: | |
Animal models | LRRK2G2019S knock-in mice and wild-type littermates (C57BL/6 background) |
Preparation Method | Mice were injected unilaterally with tau paired helical filaments (PHFs) derived from Alzheimer’s disease brains into the hippocampus and overlying cortex at 3–4 months of age. One week prior to injection, mice were placed on a control diet or a diet containing the LRRK2 kinase inhibitor MLi-2 at doses of 8mg/kg or 45mg/kg. Mice were maintained on the diet for 6 months post-injection before sacrifice and brain tissue analysis. |
Dosage form | 8mg/kg/day or 45mg/kg/day; administered orally via diet. |
Applications | MLi-2 reduced total and phosphorylated LRRK2 (pS935) levels in kidney tissue, indicating target engagement. It induced enlargement of type II pneumocytes in the lungs, consistent with known LRRK2 inhibition-related morphological changes. In LRRK2G2019S mice, MLi-2 reversed the mutation-associated acceleration of tau pathology progression, particularly in cortical brain regions, without significantly affecting tau pathology in wild-type mice. These effects were more pronounced at 6 months post-injection and with the higher dose (45mg/kg/day), suggesting a dose- and time-dependent therapeutic effect in LRRK2 mutation carriers. |
References: | |
| Cas No. | 1627091-47-7 | SDF | |
| 别名 | REL-3-[6-[(2R,6S)-2,6-二甲基-4-吗啉基]-4-嘧啶基]-5-[(1-甲基环丙基)氧基]-1H-吲唑 | ||
| Canonical SMILES | C[C@@](C1)([H])O[C@](C)([H])CN1C2=CC(C3=NNC4=CC=C(OC5(C)CC5)C=C43)=NC=N2 | ||
| 分子式 | C21H25N5O2 | 分子量 | 379.46 |
| 溶解度 | DMSO : ≥ 26 mg/mL (68.52 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.6353 mL | 13.1766 mL | 26.3532 mL |
| 5 mM | 0.5271 mL | 2.6353 mL | 5.2706 mL |
| 10 mM | 0.2635 mL | 1.3177 mL | 2.6353 mL |
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| % DMSO % % Tween 80 % saline | ||||||||||
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