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| Targets |
PARG (poly(ADP-ribose) glycohydrolase). PARG is the primary enzyme responsible for the degradation of poly(ADP-ribose) (PAR) chains, which are synthesized by PARP enzymes in response to DNA damage. By hydrolyzing PAR, PARG plays a critical role in the dynamic regulation of the DNA damage response, chromatin remodeling, and cellular metabolism. PDD00017273 inhibits PARG with an IC50 of 26 nM and a KD of 1.45 nM. The compound exhibits >350-fold selectivity for PARG over a panel of ion channels, enzymes, and receptors, including PARP1 and ARH3. PDD00017273 does not inhibit five common cytochrome P450 enzymes at 10 μM, indicating a favorable selectivity profile. By inhibiting PARG, PDD00017273 prevents PAR degradation, leading to persistent PAR accumulation and prolonged DNA damage signaling. This mechanism sensitizes cancer cells to DNA-damaging agents and radiotherapy.
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| ln Vitro |
PDD 00017273 is a strong PARG reagent with a KD of 1.45 nM and an IC50 of 26 nM. Five common cytochrome P450 enzymes are not inhibited by PDD 00017273 (10 μM). Following DNA damage, PDD 00017273 (30 μM) suppresses NAD/H through PARG and increases the intensity of phosphorylated H2AX (γH2AX). ZR-75-1 cells tagged with wild-type BRCA1 and BRCA2 are inhibited by PDD 00017273, but MDA-MB-436 cells labeled with 5396 + 1G>A in BRCA1 are only marginally affected [1]. In MCF7 cells, the breakdown of PAR medium is inhibited by PDD 00017273 (0.3 μM). Additionally, PDD 00017273 (0.3 μM) lowers the latency of BARD1, BRCA2, PALB2, FAM175A, and BRCA1. Homologous recombination (HR) is necessary for the repair of DNA damage caused by PDD 00017273, which also slows replication forks [2].
PDD00017273 is a potent PARG inhibitor with an IC50 of 26 nM and a KD of 1.45 nM. Following DNA damage, PDD00017273 (30 μM) suppresses NAD⁺/H⁺ through PARG and increases the intensity of phosphorylated H2AX (γH2AX), a marker of DNA double-strand breaks. In ZR-75-1 cells with wild-type BRCA1 and BRCA2, PDD00017273 inhibits cell growth, but MDA-MB-436 cells with a BRCA1 mutation (5396+1G>A) are only marginally affected, suggesting that the compound's activity may be dependent on homologous recombination repair proficiency. In MCF7 cells, PDD00017273 (0.3 μM) inhibits the breakdown of PAR medium. Additionally, PDD00017273 (0.3 μM) lowers the latency of BRCA1, BRCA2, PALB2, FAM175A, and BARD1 proteins. Homologous recombination (HR) is necessary for the repair of DNA damage caused by PDD00017273, which also slows replication forks. PDD00017273 is a radiosensitizing agent with anti-tumor activity, particularly for the study of epithelial ovarian cancer. |
| ln Vivo |
PDD00017273 has been studied in vivo for its anti-tumor and radiosensitizing effects. The compound is a potent PARG inhibitor that has been investigated for the treatment of epithelial ovarian cancer. By inhibiting PARG, PDD00017273 sensitizes tumors to DNA-damaging agents and radiotherapy. The compound's ability to suppress NAD⁺/H⁺ through PARG and increase γH2AX levels following DNA damage supports its role as a radiosensitizer. Detailed in vivo pharmacokinetic and pharmacodynamic data are limited in publicly available sources, but PDD00017273 is recognized as a promising tool for studying PARG biology and validating PARG as a therapeutic target in cancer. PDD00017273 is primarily used in cancer research to study DNA repair mechanisms and develop combination therapies with genotoxic agents.
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| Enzyme Assay |
PARG enzyme activity assays are performed using recombinant PARG enzyme and a fluorescent or radiolabeled PAR substrate. The enzyme is incubated with the substrate in assay buffer (50 mM Tris-HCl pH 7.5, 100 mM NaCl, 1 mM DTT, 0.01% Triton X-100) at 37°C for 30-60 minutes. The hydrolysis of PAR is quantified by measuring the release of ADP-ribose or by fluorescence polarization. PDD00017273 is serially diluted in DMSO and added to the reaction mixture. The IC50 for PDD00017273 is 26 nM. The KD is 1.45 nM. Each concentration is tested in duplicate, and IC50 values are calculated by non-linear regression analysis. Appropriate positive controls (e.g., known PARG inhibitors) and vehicle controls are included to validate the assay.
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| Cell Assay |
Cellular PARG inhibition is evaluated in cancer cell lines, including ZR-75-1 (BRCA1/2 wild-type) and MDA-MB-436 (BRCA1 mutant) cells. Cells are cultured in appropriate media (e.g., RPMI-1640 or DMEM with 10% FBS) at 37°C with 5% CO₂ and treated with PDD00017273 at concentrations ranging from 0.1 to 30 μM for 1-24 hours. PARG activity in cell lysates is measured using enzymatic assays. PAR levels are assessed by Western blotting using anti-PAR antibodies. DNA damage is evaluated by measuring γH2AX foci formation via immunofluorescence or Western blotting. Cell viability and proliferation are assessed using MTT or CellTiter-Glo assays. Homologous recombination repair efficiency is assessed using DR-GFP or similar reporter assays. Each experiment includes vehicle controls (DMSO) and appropriate positive controls (e.g., known PARP inhibitors like olaparib).
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| Animal Protocol |
In vivo efficacy of PDD00017273 is evaluated in mouse xenograft models using cancer cell lines, particularly those from epithelial ovarian cancer. Tumor cells are implanted subcutaneously or orthotopically in immunodeficient mice. When tumors reach a predetermined size, mice are randomized into treatment and control groups. PDD00017273 is administered via intraperitoneal injection or oral gavage at doses determined by preclinical studies. The compound is formulated in appropriate vehicles (e.g., DMSO/PEG300/Tween 80). Tumor growth is monitored by caliper measurements or bioluminescence imaging. Body weight and clinical signs are monitored throughout the study to assess tolerability. At study endpoint, tumors are harvested for histopathological analysis and biochemical assays (PAR levels, γH2AX, DNA damage markers). Sample sizes typically range from 6-10 animals per group.
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| ADME/Pharmacokinetics |
Molecular Weight: 514.62 (free base), 551.08 (HCl salt). Formula: C23H26N6O4S2·HCl. CAS No.: 1945950-21-9. Appearance: White to light yellow solid powder. LogP: 1.7. Solubility: DMSO. Storage: Powder at -20°C; In solvent at -80°C for 6 months; -20°C for 1 month. Purity: ≥98%. PDD00017273 is a novel, potent, and selective PARG inhibitor with an IC50 of 26 nM and a KD of 1.45 nM. PDD00017273 exhibits >350-fold selectivity for PARG over PARP1 and ARH3.
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| Toxicity/Toxicokinetics |
No comprehensive toxicology data are publicly available for PDD00017273. The compound is intended for research use only and has not undergone full preclinical toxicology evaluation required for clinical development. As a PARG inhibitor, potential toxicities may include effects on DNA repair and cellular metabolism. The compound's selectivity for PARG over PARP1 and other enzymes may reduce off-target toxicities. Standard toxicity studies would include acute toxicity assessment in rodents, repeated dose toxicity studies (14-day and 28-day), and genotoxicity screening (Ames test, micronucleus assay). PDD00017273 is for research use only and not for human therapeutic use.
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| References |
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| Additional Infomation |
PDD00017273 is also known as PDD-00017273, PDD 00017273, PDD17273, and PDD-17273. Its IUPAC name is 1-[(1,3-Dimethyl-1H-pyrazol-5-yl)methyl]-1,2,3,4-tetrahydro-N-(1-methylcyclopropyl)-3-[(2-methyl-5-thiazolyl)methyl]-2,4-dioxo-6-quinazolinesulfonamide. PDD00017273 is a potent and selective PARG inhibitor with an IC50 of 26 nM. PDD00017273 is a radiosensitizing agent with anti-tumor activity, particularly for the study of epithelial ovarian cancer. PDD00017273 is primarily used in cancer research to study DNA repair mechanisms and develop combination therapies with genotoxic agents. No clinical trials have been reported for this compound. PDD00017273 is for research use only.
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| Molecular Formula |
C23H26N6O4S2
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| Molecular Weight |
514.6203
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| Exact Mass |
514.145
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| CAS # |
1945950-21-9
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| Related CAS # |
1945950-21-9;
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| Appearance |
White to light yellow solid powder
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| LogP |
1.7
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| SMILES |
S(C1C=CC2=C(C(N(CC3=CN=C(C)S3)C(N2CC2=CC(C)=NN2C)=O)=O)C=1)(NC1(C)CC1)(=O)=O
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| InChi Key |
PIBCFKLPKFMUHX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H26N6O4S2.ClH/c1-14-9-16(27(4)25-14)12-28-20-6-5-18(35(32,33)26-23(3)7-8-23)10-19(20)21(30)29(22(28)31)13-17-11-24-15(2)34-17/h5-6,9-11,26H,7-8,12-13H2,1-4H31H
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| Chemical Name |
1-[(1,3-Dimethyl-1H-pyrazol-5-yl)methyl]-1,2,3,4-tetrahydro-N-(1-methylcyclopropyl)-3-[(2-methyl-5-thiazolyl)methyl]-2,4-dioxo-6-quinazolinesulfonamide hydrochloride
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| Synonyms |
PDD00017273 HCl PDD-00017273 PDD 00017273 PDD17273 PDD-17273 PDD 17273
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~25 mg/mL (~48.58 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.86 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.86 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.86 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9432 mL | 9.7159 mL | 19.4318 mL | |
| 5 mM | 0.3886 mL | 1.9432 mL | 3.8864 mL | |
| 10 mM | 0.1943 mL | 0.9716 mL | 1.9432 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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