PGMI-004A
目录号 : GC33387
PGMI-004A是一种有效的磷酸甘油酸变位酶1(PGAM1)抑制剂，IC50为13.1μM。
Cas No.:1313738-90-7
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
Cell experiment: | For adherent cell viability assay such as H1299 cells with trypan blue exclusion, 5×104 cells are seeded in 6-well plate 24 h before the assay starts and are cultured at 37°C. 24 h after seeding, cells are treated with PGMI-004A (5, 10, 20, and 40 μM) and incubated at 37°C for indicated times. Cell viability is determined by counting drug-treated cells compared to DMSO-treated control cells with trypan blue exclusion under a microscope (×40). For MTT cell viability assay of adherent cells, 5×103 cells are seeded in 96-well plate 24 h before the assay starts and are cultured at 37°C. 24 h after seeding, cells are treated with PGMI-004A and incubated at 37°C for 3 days. Cell viability is determined by using CellTiter96Aqueous One solution proliferation kit[1]. |
Animal experiment: | Mice[1]Nude mice (female 6-8-week-old) are subcutaneously injected with 10×106 H1299 cells harboring empty vector on the left flank, and cells with stable knockdown of endogenous hPGAM1 on the right flank, respectively. The tumors are harvested and weighed at the experimental endpoint, and the masses of tumors (g) derived from cells with and without stable knockdown of endogenous hPGAM1 in both flanks of each mouse are compared. Statistical analyses are performed by comparison in relation to the control group with a two-tailed paired Student’s ttest. For drug evaluation of PGMI-004A using xenograft mice, PGMI-004A is administered by daily i.p. injection at a dose of 100 mg/kg from 6 days after subcutaneous injection of H1299 cells on right flank of each mouse. Tumor growth is recorded by measurement of two perpendicular diameters of the tumors over a 3-week course[1]. |
References: [1]. Hitosugi T, et al. Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. Cancer Cell. 2012 Nov 13;22(5):585-600. | |
PGMI-004A is a potent phosphoglycerate mutase 1 (PGAM1) inhibitor with an IC50 of 13.1 μM.
PGMI-004A inhibits PGAM1 with an IC50 of approximately 13.1 μM and the Kd value of the PGMI-004A-PGAM1 interaction is determined to be 7.2±0.7 μM from fluorescence-based binding assay. PGMI-004A may allosterically modulate the enzyme activity of PGAM1. The Ki value is determined to be 3.91±2.50 μM using Dixon plot analysis. The Kd value for protein-ligand interaction is calculated to be 9.4±2.0 μM. Inhibition of PGAM1 activity by PGMI-004A (20 μM) treatment results in decreased 2-PG and increased 3-PG levels in H1299 cells, which could be rescued by treatment with methyl-2-PG. Treatment with PGMI-004A (20 μM) results in significantly reduced lactate production that is rescued by methyl-2-PG treatment, but has no significant effect on intracellular ATP levels. PGMI-004A (20 μM) treatment results in decreased oxidative PPP flux and NADPH/NADP+ratio, as well as reduced biosynthesis of lipids and RNA, and cell proliferation in H1299 cells. PGMI-004A treatment results in decreased cell proliferation of diverse human cancer and leukemia cells, but not control human dermal fibroblasts (HDF), human foreskin fibroblasts (HFF), human HaCaT keratinocyte cells and human melanocyte PIG1 cells, suggesting minimal non-specific toxicity of PGMI-004A in normal, proliferating human cells[1].
The xenograft experiment is performed by injecting H1299 cells to nude mice. Six days post-injection, mice are divided into two groups (n=8/group) and treated with either PGMI-004A (100mg/kg/day) or vehicle for 21 days. PGMI-004A treatment results in significantly decreased tumor growth and tumor size in treated mice compared with mice receiving vehicle control. Moreover, treatment with PGMI-004A effectively inhibits PGAM1 enzyme activity in tumors in vivo in resected tumors from xenograft nude mice[1].
[1]. Hitosugi T, et al. Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. Cancer Cell. 2012 Nov 13;22(5):585-600.
| Cas No. | 1313738-90-7 | SDF | |
| Canonical SMILES | O=S(C(C=C1C2=O)=C(O)C(O)=C1C(C3=C2C=CC=C3)=O)(NC4=CC=C(C(F)(F)F)C=C4)=O | ||
| 分子式 | C21H12F3NO6S | 分子量 | 463.38 |
| 溶解度 | DMSO : ≥ 125 mg/mL (269.76 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 | 2.1581 mL | 10.7903 mL | 21.5806 mL |
| 5 mM | 0.4316 mL | 2.1581 mL | 4.3161 mL |
| 10 mM | 0.2158 mL | 1.079 mL | 2.1581 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。
Xanthone derivatives as phosphoglycerate mutase 1 inhibitors: Design, synthesis, and biological evaluation
Bioorg Med Chem 2018 May 1;26(8):1961-1970.PMID:29530347DOI:10.1016/j.bmc.2018.02.044.
Phosphoglycerate mutase 1 (PGAM1) is a glycolytic enzyme that dynamically converts 3-phosphoglycerate (3PG) to 2-phosphoglycerate (2PG), which was upregulated to coordinate glycolysis, pentose phosphate pathway (PPP) and serine biosynthesis to promote cancer cell proliferation and tumor growth in a variety of cancers. However, only a few inhibitors of PGAM1 have been reported with poor molecular or cellular efficacy. In this paper, a series of xanthone derivatives were discovered as novel PGAM1 inhibitors through scaffold hopping and sulfonamide reversal strategy based on the lead compound PGMI-004A. Most xanthone derivatives showed higher potency against PGAM1 than PGMI-004A and exhibited moderate anti-proliferation activity on different cancer cell lines.
The Design and Synthesis of N-Xanthone Benzenesulfonamides as Novel Phosphoglycerate Mutase 1 (PGAM1) Inhibitors
Molecules 2018 Jun 8;23(6):1396.PMID:29890679DOI:10.3390/molecules23061396.
Upregulation of phosphoglycerate mutase 1 (PGAM1) has been identified as one common phenomenon in a variety of cancers. Inhibition of PGAM1 provides a new promising therapeutic strategy for cancer treatment. Herein, based on our previous work, a series of new N-xanthone benzenesulfonamides were discovered as novel PGAM1 inhibitors. The representative molecule 15h, with an IC50 of 2.1 μM, showed an enhanced PGAM1 inhibitory activity and higher enzyme inhibitory specificity compared to PGMI-004A, as well as a slightly improved antiproliferative activity.
Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth
Cancer Cell 2012 Nov 13;22(5):585-600.PMID:23153533DOI:10.1016/j.ccr.2012.09.020.
It is unclear how cancer cells coordinate glycolysis and biosynthesis to support rapidly growing tumors. We found that the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1), commonly upregulated in human cancers due to loss of TP53, contributes to biosynthesis regulation in part by controlling intracellular levels of its substrate, 3-phosphoglycerate (3-PG), and product, 2-phosphoglycerate (2-PG). 3-PG binds to and inhibits 6-phosphogluconate dehydrogenase in the oxidative pentose phosphate pathway (PPP), while 2-PG activates 3-phosphoglycerate dehydrogenase to provide feedback control of 3-PG levels. Inhibition of PGAM1 by shRNA or a small molecule inhibitor PGMI-004A results in increased 3-PG and decreased 2-PG levels in cancer cells, leading to significantly decreased glycolysis, PPP flux and biosynthesis, as well as attenuated cell proliferation and tumor growth.
Synthesis and biological evaluation of anthraquinone derivatives as allosteric phosphoglycerate mutase 1 inhibitors for cancer treatment
Eur J Med Chem 2019 Apr 15;168:45-57.PMID:30798052DOI:10.1016/j.ejmech.2019.01.085.
Phosphoglycerate mutase 1 (PGAM1) coordinates glycolysis, pentose phosphate pathway, and serine synthesis to promote tumor growth through the regulation of its substrate 3-phosphoglycerate (3 PG) and product 2-phosphoglycerate (2 PG). Herein, based on our previously reported PGAM1 inhibitor PGMI-004A, we have developed anthraquinone derivatives as novel allosteric PGAM1 inhibitors and the structure-activity relationship (SAR) was investigated. In addition, we determined the co-crystal structure of PGAM1 and the inhibitor 8g, demonstrating that the inhibitor was located at a novel allosteric site. Among the derivatives, compound 8t was selected for further study, with IC50 values of 0.25 and approximately 5 μM in enzymatic and cell-based assays, respectively. Mechanistically, compound 8t reduced the glycolysis and oxygen consumption rate in cancer cells, which led to decreased adenosine 5'-triphosphate (ATP) production and subsequent 5' adenosine monophosphate-activated protein kinase (AMPK) activation. The inhibitor 8t also exhibited good efficacy in delaying tumor growth in H1299 xenograft model without obvious toxicity. Taken together, this proof-of-principle work further validates PGAM1 as a potential target for cancer therapy and provides useful information on anti-tumor drug discovery targeting PGAM1.
In silico-based identification of phytochemicals as novel human phosphoglycerate mutase 1 (PGAM1) inhibitors for cancer therapy
Pak J Pharm Sci 2021 Mar;34(2(Supplementary)):665-670.PMID:34275800doi
Targeting cancer-specific metabolic and mitochondrial remodeling has emerged as a novel and selective strategy for cancer therapy during recent years. Phosphoglycerate Mutase 1 (PGAM1) is an important glycolytic enzyme that catalyzes the conversion of 3-phosphoglycerate to 2-phosphoglycerate and plays a critical role in cancer progression by coordinating glycolysis and biosynthesis. PGAM1 has been reported to be over expressed in a variety of cancer types and its inhibition results in decreased tumor growth and metastasis. Recently, there has been a growing interest in identification and characterization of novel PGAM1 inhibitors for the treatment of cancer. In the current study, in silico tools were used to find out natural inhibitors of PGAM1. For docking studies, a database of 5006 phytochemicals were docked against PGAM1, using MOE software in order to identify the compounds which show better binding affinities than PGMI-004A. Out of 5006 compounds screened, eight compounds (1,3-cyclopentanedione, glyflavanone B, 6-demethoxytangeretin, gnaphaliin, lantalucratin A and -(-) morelensin, abyssinin II and monotesone-A) showed significant binding affinity with PGAMI active site. Further, the eight selected compounds were evaluated for different pharmacokinetics parameters using admetSAR, the obtained results demonstrated that none of these hit compounds violated Lipinski's drug rule of 5 and all the hit compounds possess favorable ADMET properties. This study has unveiled the potential of phytochemicals that could serve as probable lead candidates for the development of PGAM1 inhibitors as anti-cancer agents.