LLY-283
目录号 : GC33184
A PRMT5 inhibitor
Cas No.:2040291-27-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
LLY-283 is an inhibitor of protein arginine methyltransferase 5 (PRMT5; IC50 = 22 nM).1 It is selective for PRMT5 over a panel of methyltransferases, including PRMT4, -6, and -7 at 1 μM. It reduces symmetric demethylation of SmBB' in MCF-7 cells (IC50 = 25 nM) and inhibits proliferation of various breast, gastric, hematological, lung, skin, and ovarian cancer cell lines (IC50s = 3-30 nM). LLY-283 (20 mg/kg) inhibits tumor growth in an A375 mouse xenograft model. It also disrupts alternative splicing events in, and inhibits proliferation and self-renewal of, patient-derived glioblastoma stem cells and increases survival in an orthotopic patient-derived xenograft (PDX) mouse model.2 See the Structural Genomics Consortium (SGC) website for more information.
1.Bonday, Z.Q., Cortez, G.S., Grogan, M.J., et al.LLY-283, a potent and selective inhibitor of arginine methyltransferase 5, PRMT5, with antitumor activityACS Med. Chem. Lett.9(7)612-617(2018) 2.Sachamitr, P., Ho, J.C., Ciamponi, F.E., et al.PRMT5 inhibition disrupts splicing and stemness in glioblastomaNat. Commun.12(1)979(2021)
| Cas No. | 2040291-27-6 | SDF | |
| Canonical SMILES | O[C@H]1[C@@H](O[C@@]([C@@H](C2=CC=CC=C2)O)([H])[C@H]1O)N3C4=NC=NC(N)=C4C=C3 | ||
| 分子式 | C17H18N4O4 | 分子量 | 342.35 |
| 溶解度 | DMSO: 250 mg/mL (730.25 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.921 mL | 14.6049 mL | 29.2099 mL |
| 5 mM | 0.5842 mL | 2.921 mL | 5.842 mL |
| 10 mM | 0.2921 mL | 1.4605 mL | 2.921 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
PRMT5 inhibition disrupts splicing and stemness in glioblastoma
Nat Commun 2021 Feb 12;12(1):979.PMID:33579912DOI:10.1038/s41467-021-21204-5.
Glioblastoma (GBM) is a deadly cancer in which cancer stem cells (CSCs) sustain tumor growth and contribute to therapeutic resistance. Protein arginine methyltransferase 5 (PRMT5) has recently emerged as a promising target in GBM. Using two orthogonal-acting inhibitors of PRMT5 (GSK591 or LLY-283), we show that pharmacological inhibition of PRMT5 suppresses the growth of a cohort of 46 patient-derived GBM stem cell cultures, with the proneural subtype showing greater sensitivity. We show that PRMT5 inhibition causes widespread disruption of splicing across the transcriptome, particularly affecting cell cycle gene products. We identify a GBM splicing signature that correlates with the degree of response to PRMT5 inhibition. Importantly, we demonstrate that LLY-283 is brain-penetrant and significantly prolongs the survival of mice with orthotopic patient-derived xenografts. Collectively, our findings provide a rationale for the clinical development of brain penetrant PRMT5 inhibitors as treatment for GBM.
[LLY-283 inhibits proliferation and metastasis of head and neck squamous cell carcinoma by targeting PRMT5]
Shanghai Kou Qiang Yi Xue 2022 Apr;31(2):142-147.PMID:36110070doi
Purpose: To explore the effect of LLY-283 on the biological behavior of Head and neck squamous cell carcinoma(HNSCC) proliferation and metastasis through protein arginine methyltransferase 5(PRMT5). Methods: TCGA database was used to analyze the expression level of PRMT5 in HNSCC tissues and cell lines by RT-PCR and Western blot. Lentiviral technology was used to construct PRMT5 knockdown stable cell line, and analyze the effect of PRMT5 on the biological behavior of HNSCC. Drug killing experiment was used to observe the IC50 changes of LLY-283 in cell lines. Nude mouse xenograft experiments were further tested to observe the biological effects of LLY-283 on HNSCC through PRMT5. Results: PRMT5 was highly expressed in HNSCC tissues and cell lines, which promoted the proliferation and metastasis of cell lines, and reduced the IC50 value of LLY-283. LLY-283 could significantly reduce the cell proliferation and metastasis, tumor volume and Ki-67 expression in nude mice in vivo of HNSCC through PRMT5. Conclusions: LLY-283 inhibits the expression of PRMT5 and Ki-67, thereby decreases the proliferation and metastasis of HNSCC and the ability to form transplanted tumors in nude mice, exerting anti-tumor effects.
Explore the effect of LLY-283 on the ototoxicity of auditory cells caused by cisplatin: A bioinformatic analysis based on RNA-seq
J Clin Lab Anal 2022 Feb;36(2):e24176.PMID:34997776DOI:10.1002/jcla.24176.
Background: Cisplatin is a commonly used chemotherapeutic drug in clinics, and long-term application will lead to hearing impairment. LLY-283, an inhibitor of PRMT5, has not been reported in deafness. Our study aimed to explore the mechanism of LLY-283 in hearing impairment. Materials and methods: First, we performed RNA-seq (cisplatin in the experimental group and DMSO in the control group) to obtain the biological processes mainly involved in differentially expressed genes (DEGs). CCK-8 and LDH experiments were used to observe the effect of LLY-283 on cisplatin-induced auditory cell injury. ROS experiment was used to monitor the impact of LLY-283 on oxidative damage of auditory cells. Effect of LLY-283 on apoptosis of auditory cells detected by TUNEL experiment. PCR and Western blotting were used to detect the expression of genes and proteins related to auditory cell apoptosis in LLY-283 cells. Meanwhile, we explored the effect of LLY-283 on the expression of PRMT5 in cisplatin-induced hearing impaired cells at RNA and protein levels. Results: Biological process analysis showed that DEGs were mainly enriched in the apoptotic process involved in morphogenesis (-Log10 P = 3.71). CCK-8 and LDH experiments confirmed that LLY-283 could save cisplatin-induced auditory cell injury. ROS experiments confirmed that LLY-283 could rescue cisplatin-induced oxidative damage to auditory cells. TUNEL experiments confirmed that LLY-283 could protect cisplatin-induced apoptosis of auditory cells. Meanwhile, LLY-283 could inhibit the expression of PRMT5 in auditory cells induced by cisplatin. Conclusion: LLY-283 can rescue cisplatin-induced auditory cell apoptosis injury. LLY-283 can inhibit the increase in PRMT5 expression induced by cisplatin.
LLY-283, a Potent and Selective Inhibitor of Arginine Methyltransferase 5, PRMT5, with Antitumor Activity
ACS Med Chem Lett 2018 Apr 23;9(7):612-617.PMID:30034588DOI:10.1021/acsmedchemlett.8b00014.
Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the formation of symmetric dimethylarginine in a number of nuclear and cytoplasmic proteins. Although the cellular functions of PRMT5 have not been fully unraveled, it has been implicated in a number of cellular processes like RNA processing, signal transduction, and transcriptional regulation. PRMT5 is ubiquitously expressed in most tissues and its expression has been shown to be elevated in several cancers including breast cancer, gastric cancer, glioblastoma, and lymphoma. Here, we describe the identification and characterization of a novel and selective PRMT5 inhibitor with potent in vitro and in vivo activity. Compound 1 (also called LLY-283) inhibited PRMT5 enzymatic activity in vitro and in cells with IC50 of 22 ± 3 and 25 ± 1 nM, respectively, while its diastereomer, compound 2 (also called LLY-284), was much less active. Compound 1 also showed antitumor activity in mouse xenografts when dosed orally and can serve as an excellent probe molecule for understanding the biological function of PRMT5 in normal and cancer cells.
A PRMT5 inhibitor protects against noise-induced hearing loss by alleviating ROS accumulation
Ecotoxicol Environ Saf 2022 Sep 15;243:113992.PMID:35994911DOI:10.1016/j.ecoenv.2022.113992.
The aim of this study was to investigate the effect of LLY-283, a selective inhibitor of protein arginine methyltransferase 5 (PRMT5), on a noise-induced hearing loss (NIHL) mouse model and to identify a potential target for a therapeutic intervention against NIHL. Eight-week-old male C57BL/6 mice were used. The auditory brainstem response was measured 2 days after noise exposure. The apoptosis of hair cells (HCs) was detected by caspase-3/7 staining, whereas the accumulation of reactive oxygen species (ROS) was measured by 4-HNE staining. We demonstrated that the death of HCs and loss of cochlear synaptic ribbons induced by noise exposure could be significantly reduced by the presence of LLY-283. LLY-283 pretreatment before noise exposure notably decreased 4-HNE and caspase-3/7 levels in the cochlear HCs. We also noticed that the number of spiral ganglion neurons (SGNs) was notably increased after LLY-283 pretreatment. Furthermore, we showed that LLY-283 could increase the expression level of p-AKT in the SGNs. The underlying mechanism involves alleviation of ROS accumulation and activation of the PI3K/AKT pathway, indicating that LLY-283 might be a potential candidate for therapeutic intervention against NIHL.