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BRD0639 Sale

目录号 : GC63731

An inhibitor of the protein-peptide interaction between PRMT5 and PBM

BRD0639 Chemical Structure

Cas No.:2760881-74-9

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥1,412.00
现货
5 mg
¥1,350.00
现货
10 mg
¥2,250.00
现货
25 mg
¥4,500.00
现货

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Sample solution is provided at 25 µL, 10mM.

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产品描述

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)

Chemical Properties

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
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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
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Research Update

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.