UPCDC-30245
目录号 : GC64694
UPCDC-30245 是一种变构 p97 (allosteric p97) 抑制剂，IC50 约为 27 nM。UPCDC-30245 抑制 p97 突变体 N660K 的效力与野生型 (IC50=300 nM) 相似，此外对 p97 突变体 T688A 仅表现出 3 倍的耐药性。UPCDC-30245可用于癌症研究。
Cas No.:1883351-01-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
UPCDC-30245 is an allosteric p97 inhibitor with an IC50 of approximately 27 nM[1]. UPCDC-30245 inhibits the p97 mutant N660K similar to wild type (WT; IC50=300 nM) and shows 3-fold resistance for p97 mutant T688A[2]. UPCDC-30245 can be used in the research of cancer[1][2][3].
UPCDC-30245 binds at the junction between the D1 dan D2 domains of p97[1]. UPCDC-30245 inhibits cell proliferation in HeLa, A549, BxPC-3, PRMI8226, MM1S, HCT116 cells, and appears more potent in HT29 cells[2].UPCDC-30245 (0.01-100 μM) shows anti-proliferative effects on parental and CB-5083 resistant HCT116 cell lines that harbor a new p97 double mutation (D649A/T688A)[2].UPCDC-30245 (4 μm; 2, 6, 10, 18, 24 hours; functional enrichment analysis) is not linked to pathways typically impacted by p97 inhibition, such as protein processing in the ER, UPR, and asparagine N-linked glycosylation[3].
[1]. Banerjee S, et al. 2.3 Å resolution cryo-EM structure of human p97 and mechanism of allosteric inhibition. Science. 2016 Feb 19;351(6275):871-5.
[2]. Wang F, et al. Allosteric p97 Inhibitors Can Overcome Resistance to ATP-Competitive p97 Inhibitors for Potential Anticancer Therapy. ChemMedChem. 2020 Apr 20;15(8):685-694.
[3]. Wang F, et al. Temporal proteomics reveal specific cell cycle oncoprotein downregulation by p97/VCP inhibition. Cell Chem Biol. 2021 Nov 23:S2451-9456(21)00482-7.
| Cas No. | 1883351-01-6 | SDF | Download SDF |
| 分子式 | C28H38FN5 | 分子量 | 463.63 |
| 溶解度 | 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 | 2.1569 mL | 10.7845 mL | 21.5689 mL |
| 5 mM | 0.4314 mL | 2.1569 mL | 4.3138 mL |
| 10 mM | 0.2157 mL | 1.0784 mL | 2.1569 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。
The p97 Inhibitor UPCDC-30245 Blocks Endo-Lysosomal Degradation
Pharmaceuticals (Basel) 2022 Feb 7;15(2):204.PMID:35215314DOI:10.3390/ph15020204.
The diverse modes of action of small molecule inhibitors provide versatile tools to investigate basic biology and develop therapeutics. However, it remains a challenging task to evaluate their exact mechanisms of action. We identified two classes of inhibitors for the p97 ATPase: ATP competitive and allosteric. We showed that the allosteric p97 inhibitor, UPCDC-30245, does not affect two well-known cellular functions of p97, endoplasmic-reticulum-associated protein degradation and the unfolded protein response pathway; instead, it strongly increases the lipidated form of microtubule-associated proteins 1A/1B light chain 3B (LC3-II), suggesting an alteration of autophagic pathways. To evaluate the molecular mechanism, we performed proteomic analysis of UPCDC-30245 treated cells. Our results revealed that UPCDC-30245 blocks endo-lysosomal degradation by inhibiting the formation of early endosome and reducing the acidity of the lysosome, an effect not observed with the potent p97 inhibitor CB-5083. This unique effect allows us to demonstrate UPCDC-30245 exhibits antiviral effects against coronavirus by blocking viral entry.
Allosteric p97 Inhibitors Can Overcome Resistance to ATP-Competitive p97 Inhibitors for Potential Anticancer Therapy
ChemMedChem 2020 Apr 20;15(8):685-694.PMID:32162487DOI:10.1002/cmdc.201900722.
A major challenge of targeted cancer therapy is the selection for drug-resistant mutations in tumor cells leading to loss of treatment effectiveness. p97/VCP is central regulator of protein homeostasis and a promising anticancer target because of its vital role in cell growth and survival. One ATP-competitive p97 inhibitor, CB-5083, has entered clinical trials. Selective pressure on HCT116 cells dosed with CB-5083 identified five different resistant mutants. Identification of p97 inhibitors with different mechanisms of action would offer the potential to overcome this class of resistance mutations. Our results demonstrate that two CB-5083 resistant p97 mutants, N660 K and T688 A, were also resistant to several other ATP-competitive p97 inhibitors, whereas inhibition by two allosteric p97 inhibitors NMS-873 and UPCDC-30245 were unaffected by these mutations. We also established a CB-5083 resistant cell line that harbors a new p97 double mutation (D649 A/T688 A). While CB-5083, NMS-873, and UPCDC-30245 all effectively inhibited proliferation of the parental HCT116 cell line, NMS-873 and UPCDC-30245 were 30-fold more potent in inhibiting the CB-5083 resistant D649 A/T688 A double mutant than CB-5083. Our results suggest that allosteric p97 inhibitors are promising alternatives when resistance to ATP-competitive p97 inhibitors arises during anticancer treatment.