COH000
(Synonyms: (1R,4S)-二甲基1-((R)-1-(苯基氨基)-2-(对甲苯基)乙基)-7-氧杂二环[2.2.1]庚-2,5-二烯-2,3-二羧酸) 目录号 : GC33039
An inhibitor of SUMO-activating enzyme
Cas No.:1534358-79-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
COH000 is an inhibitor of SUMO-activating enzyme (SAE; IC50 = 0.2 ?M), a heterodimer composed of SAE1 and SAE2.1 It is selective for SAE over ubiquitin-activating enzyme (UAE) and NEDD8-activating enzyme (NAE) at 10 ?M. COH000 induces degradation of SAE2 in HCT116 human colon cancer cells. COH000 (10 mg/kg) induces intratumoral apoptosis, decreases intratumoral c-Myc expression, and reduces tumor growth in an HCT116 mouse xenograft model.
1.Li, Y.-J., Du, L., Wang, J., et al.Allosteric inhibition of ubiquitin-like modifications by a class of inhibitor of SUMO-activating enzymeCell Chem. Biol.26(2)278-288(2019)
| Cas No. | 1534358-79-6 | SDF | |
| 别名 | (1R,4S)-二甲基1-((R)-1-(苯基氨基)-2-(对甲苯基)乙基)-7-氧杂二环[2.2.1]庚-2,5-二烯-2,3-二羧酸 | ||
| Canonical SMILES | CC(C=C1)=CC=C1C[C@@H](NC2=CC=CC=C2)[C@]34C(C(OC)=O)=C(C(OC)=O)[C@@H](O4)C=C3 | ||
| 分子式 | C25H25NO5 | 分子量 | 419.47 |
| 溶解度 | DMSO : 35.71 mg/mL (85.13 mM);Water : < 0.1 mg/mL (insoluble) | 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 | 2.384 mL | 11.9198 mL | 23.8396 mL |
| 5 mM | 0.4768 mL | 2.384 mL | 4.7679 mL |
| 10 mM | 0.2384 mL | 1.192 mL | 2.384 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。
Molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme
Nat Commun 2018 Dec 4;9(1):5145.PMID:30514846DOI:10.1038/s41467-018-07015-1.
E1 enzymes activate ubiquitin (Ub) and ubiquitin-like modifiers (Ubls) in the first step of Ub/Ubl conjugation cascades and represent potential targets for therapeutic intervention in cancer and other life-threatening diseases. Here, we report the crystal structure of the E1 enzyme for the Ubl SUMO in complex with a recently discovered and highly specific covalent allosteric inhibitor (COH000). The structure reveals that COH000 targets a cryptic pocket distinct from the active site that is completely buried in all previous SUMO E1 structures and that COH000 binding to SUMO E1 is accompanied by a network of structural changes that altogether lock the enzyme in a previously unobserved inactive conformation. These structural changes include disassembly of the active site and a 180° rotation of the catalytic cysteine-containing SCCH domain, relative to conformational snapshots of SUMO E1 poised to catalyze adenylation. Altogether, our study provides a molecular basis for the inhibitory mechanism of COH000 and its SUMO E1 specificity, and also establishes a framework for potential development of molecules targeting E1 enzymes for other Ubls at a cryptic allosteric site.
Critical Non-Covalent Binding Intermediate for an Allosteric Covalent Inhibitor of SUMO E1
J Phys Chem Lett 2023 Mar 23;14(11):2792-2799.PMID:36898086DOI:10.1021/acs.jpclett.3c00253.
Post-translational modifications by small ubiquitin-like modifiers (SUMOs) are dysregulated in many types of cancers. The SUMO E1 enzyme has recently been suggested as a new immuno-oncology target. COH000 was recently identified as a highly specific allosteric covalent inhibitor of SUMO E1. However, a marked discrepancy was found between the X-ray structure of the covalent COH000-bound SUMO E1 complex and the available structure-activity relationship (SAR) data of inhibitor analogues due to unresolved noncovalent protein-ligand interactions. Here, we have investigated noncovalent interactions between COH000 and SUMO E1 during inhibitor dissociation through novel Ligand Gaussian accelerated molecular dynamics (LiGaMD) simulations. Our simulations have identified a critical low-energy non-covalent binding intermediate conformation of COH000 that agreed excellently with published and new SAR data of the COH000 analogues, which were otherwise inconsistent with the X-ray structure. Altogether, our biochemical experiments and LiGaMD simulations have uncovered a critical non-covalent binding intermediate during allosteric inhibition of the SUMO E1 complex.