PTC299
(Synonyms: PTC-299) 目录号 : GC65335
A DHODH inhibitor
Cas No.:1256565-36-2
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
Emvododstat is an inhibitor of dihydroorotate dehydrogenase (DHODH).1 It inhibits DHODH by 89% in HeLa cells when used at a concentration of 100 nM. Emvododstat inhibits hypoxia-induced VEGF-A synthesis in HeLa cells (EC50 = 1.64 nM). It inhibits viral replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), hepatitis C virus (HCV) replicon genotype 1b, poliomyelitis virus, Rift Valley fever (RVF) virus, and Ebola virus in Vero, Huh7, HeLa, HeLa, and Vero 76 cells, respectively (EC50s = 2.6, 36, 0.57, 13, and 9.1 nM, respectively).2 Emvododstat inhibits production of IL-17F and IL-17A induced by CD3 and CD28 in Th17 cells in a concentration-dependent manner.
1.Cao, L., Weetall, M., Trotta, C., et al.Targeting of hematologic malignancies with PTC299, a novel potent inhibitor of dihydroorotate dehydrogenase with favorable pharmaceutical propertiesMol. Cancer Ther.18(1)3-16(2019) 2.Luban, J., Sattler, R.A., Mühlberger, E., et al.The DHODH inhibitor PTC299 arrests SARS-CoV-2 replication and suppresses induction of inflammatory cytokinesVirus Res.292198246(2021)
| Cas No. | 1256565-36-2 | SDF | Download SDF |
| 别名 | PTC-299 | ||
| 分子式 | C25H20Cl2N2O3 | 分子量 | 467.34 |
| 溶解度 | DMSO : 50 mg/mL (106.99 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 | 2.1398 mL | 10.6988 mL | 21.3977 mL |
| 5 mM | 0.428 mL | 2.1398 mL | 4.2795 mL |
| 10 mM | 0.214 mL | 1.0699 mL | 2.1398 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。
An update of anti-viral treatment of COVID-19
Turk J Med Sci 2021 Dec 17;51(SI-1):3372-3390.PMID:34391321DOI:10.3906/sag-2106-250.
Background/aim: Currently there is not an effective antiviral treatment for COVID-19, but a large number of drugs have been evaluated since the beginning of the pandemic, and many of them have been used for the treatment of COVID-19 despite the preliminary or conflicting results of the clinical trials. We aimed to review and summarize all of the current knowledge on the antivirals for COVID-19 Results: There are 2 main drug groups for SARS-CoV-2: agents that target proteins or RNA of the virus or interfere with proteins or biological processes in the host that support the virus. The main drug groups include inhibitors of viral entry into the human cell (convalescent plasma, monoclonal antibodies, nanobodies, mini proteins, human soluble ACE-2, camostat, dutasteride, proxalutamide, bromhexin, hydroxychloroquine, umifenovir nitazoxanid, niclosamide, lactoferrin), inhibitors of viral proteases (lopinavir/ritonavir, PF-07321332, PF-07304814, GC376), inhibitors of viral RNA (remdesivir, favipiravir, molnupiravir, AT-527, merimepodib, PTC299), inhibitors of host proteins supporting virus (plitidepsin, fluvoxamine, ivermectin), and agents supporting host natural immunity (Interferons). Conclusion: When taking into account the results of all the available laboratory and clinical trials on the subject, monoclonal antibodies seem to be the most effective treatment for COVID-19 at the moment, and high-titer convalescent plasma also could be effective when administered during the early phase of the disease. As lopinavir/ritonavir, hydroxychloroquine, merimepodib, and umifenovir were found to be ineffective in RCTs, they should not be used. Additional studies are needed to define the role of remdesivir, favipiravir, interferons, ivermectin, dutasteride, proxulutamide, fluvoxamine, bromhexine, nitazoxanide, and niclosamid in the treatment of COVID-19. Finally, the results of phase trials are waited to learn whether or not the newer agents such as molnupiravir, PF-07321332, PF-07304814, plitidepsin and AT-527 are effective in the treatment of COVID-19.
The DHODH inhibitor PTC299 arrests SARS-CoV-2 replication and suppresses induction of inflammatory cytokines
Virus Res 2021 Jan 15;292:198246.PMID:33249060DOI:10.1016/j.virusres.2020.198246.
The coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-COV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally bioavailable compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine nucleotide biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS-COV-2 replication (EC50 range, 2.0-31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known DHODH requirements for immunomodulatory cytokine production, PTC299 inhibited the production of interleukin (IL)-6, IL-17A (also called IL-17), IL-17 F, and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and previously established favorable pharmacokinetic and human safety profiles render PTC299 a promising therapeutic for COVID-19.
The DHODH Inhibitor PTC299 Arrests SARS-CoV-2 Replication and Suppresses Induction of Inflammatory Cytokines
bioRxiv 2020 Aug 5;2020.08.05.238394.PMID:32793904DOI:10.1101/2020.08.05.238394.
The coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-CoV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally available compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS CoV-2 replication (EC 50 range, 2.0 to 31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known DHODH requirements for immunomodulatory cytokine production, PTC299 inhibited the production of interleukin (IL)-6, IL-17A (also called IL-17), IL-17F, and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and previously established favorable pharmacokinetic and human safety profiles render PTC299 a promising therapeutic for COVID-19.
SAR studies toward discovery of emvododstat (PTC299), a potent dihydroorotate dehydrogenase (DHODH) inhibitor
Eur J Med Chem 2022 Dec 15;244:114826.PMID:36242990DOI:10.1016/j.ejmech.2022.114826.
Dihydroorotate dehydrogenase (DHODH) is the enzyme that catalyzes a rate-determining step during the de novo synthesis of uridine, an important source of cellular pyrimidine nucleotides. Ability to modulate the activity of this enzyme may be used to control diseases associated with rapid, out-of-control cell growth in oncology, immunology, and virology. Emvododstat (PTC299) is a tetrahydro-β-carboline DHODH inhibitor discovered through the GEMS technology (Gene Expression Modulation by Small-Molecules). Described in this paper is the lead optimization campaign that culminated in the discovery of this highly potent DHODH inhibitor.
Targeting of Hematologic Malignancies with PTC299, A Novel Potent Inhibitor of Dihydroorotate Dehydrogenase with Favorable Pharmaceutical Properties
Mol Cancer Ther 2019 Jan;18(1):3-16.PMID:30352802DOI:10.1158/1535-7163.MCT-18-0863.
PTC299 was identified as an inhibitor of VEGFA mRNA translation in a phenotypic screen and evaluated in the clinic for treatment of solid tumors. To guide precision cancer treatment, we performed extensive biological characterization of the activity of PTC299 and demonstrated that inhibition of VEGF production and cell proliferation by PTC299 is linked to a decrease in uridine nucleotides by targeting dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme for de novo pyrimidine nucleotide synthesis. Unlike previously reported DHODH inhibitors that were identified using in vitro enzyme assays, PTC299 is a more potent inhibitor of DHODH in isolated mitochondria suggesting that mitochondrial membrane lipid engagement in the DHODH conformation in situ is required for its optimal activity. PTC299 has broad and potent activity against hematologic cancer cells in preclinical models, reflecting a reduced pyrimidine nucleotide salvage pathway in leukemia cells. Archived serum samples from patients treated with PTC299 demonstrated increased levels of dihydroorotate, the substrate of DHODH, indicating target engagement in patients. PTC299 has advantages over previously reported DHODH inhibitors, including greater potency, good oral bioavailability, and lack of off-target kinase inhibition and myelosuppression, and thus may be useful for the targeted treatment of hematologic malignancies.