BRD0639
目录号 : GC63731
An inhibitor of the protein-peptide interaction between PRMT5 and PBM
Cas No.:2760881-74-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
BRD0639 is an inhibitor of the protein-peptide interaction between protein arginine methyltransferase 5 (PRMT5) and PRMT5 binding motif (PBM; IC50 = 13.8 ?M), a conserved peptide motif contained in PRMT5 substrate adaptor proteins (SAPs) that mediates SAP binding to PRMT5.1 It induces the formation of PRMT5 adducts in cells (EC50 = 3 ?M) and disrupts complex formation between PRMT5 and the SAP RIO kinase 1 (RIOK1) in permeabilized cells.
1.McKinney, D.C., McMillan, B.J., Ranaghan, M.J., et al.Discovery of a first-in-class inhibitor of the PRMT5?substrate adaptor interactionJ. Med. Chem.64(15)11148-11168(2022)
| Cas No. | 2760881-74-9 | SDF | |
| 分子式 | C21H22ClN5O4S | 分子量 | 475.95 |
| 溶解度 | DMSO : 250 mg/mL (525.27 mM; Need ultrasonic) | 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 | 2.1011 mL | 10.5053 mL | 21.0106 mL |
| 5 mM | 0.4202 mL | 2.1011 mL | 4.2021 mL |
| 10 mM | 0.2101 mL | 1.0505 mL | 2.1011 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。
Discovery of a First-in-Class Inhibitor of the PRMT5-Substrate Adaptor Interaction
J Med Chem 2021 Aug 12;64(15):11148-11168.PMID:34342224DOI:PMC9036822
PRMT5 and its substrate adaptor proteins (SAPs), pICln and Riok1, are synthetic lethal dependencies in MTAP-deleted cancer cells. SAPs share a conserved PRMT5 binding motif (PBM) which mediates binding to a surface of PRMT5 distal to the catalytic site. This interaction is required for methylation of several PRMT5 substrates, including histone and spliceosome complexes. We screened for small molecule inhibitors of the PRMT5-PBM interaction and validated a compound series which binds to the PRMT5-PBM interface and directly inhibits binding of SAPs. Mode of action studies revealed the formation of a covalent bond between a halogenated pyridazinone group and cysteine 278 of PRMT5. Optimization of the starting hit produced a lead compound, BRD0639, which engages the target in cells, disrupts PRMT5-RIOK1 complexes, and reduces substrate methylation. BRD0639 is a first-in-class PBM-competitive inhibitor that can support studies of PBM-dependent PRMT5 activities and the development of novel PRMT5 inhibitors that selectively target these functions.