PDD00017273 is a novel, potent and selective poly (ADP ribose) glycohydrolase (PARG) inhibitor with an IC50 of 26 nM. PDD00017273 exhibits >350-fold selectivity for PARG over a panel of ion channels, enzymes and receptors, including PARP1 and ARH3.
Physicochemical Properties
| Molecular Formula | C23H26N6O4S2 |
| Molecular Weight | 514.6203 |
| Exact Mass | 514.145 |
| CAS # | 1945950-21-9 |
| Related CAS # | 1945950-21-9; |
| Appearance | White to light yellow solid powder |
| LogP | 1.7 |
| 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 |
| InChi Key | PIBCFKLPKFMUHX-UHFFFAOYSA-N |
| 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 |
| 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 |
| Synonyms | PDD00017273 HCl PDD-00017273 PDD 00017273 PDD17273 PDD-17273 PDD 17273 |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| 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]. |
| References |
[1]. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to AZD2281. ACS Chem Biol. 2016 Nov 18;11(11):3179-3190. Epub 2016 Oct 12. [2]. Specific killing of DNA damage-response deficient cells with inhibitors of poly(ADP-ribose) glycohydrolase. DNA Repair (Amst). 2017 Apr;52:81-91. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~25 mg/mL (~48.58 mM) |
| 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. 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. 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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| 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 |