AG-14361
AG-14361 is a selective inhibitor of PARP-1 with Ki50 value
PARP1 is a member of PRAP family and plays an important role in many cellular processes, such as DNA repair, programmed cell death. It has been revealed that PARP1 is abnormally expressed in a variety of cancers and many PARP inhibitors have been developed as the anti-tumor drugs [1] [2] [3, 4].
AG-14361 is a potent PARP-1 inhibitor. When exposed HR and BRCA2-defective cells and parental cells to AG-14361, HR-defective cells were hypersensitive to the AG-14361 even at non-cytotoxic concentrations and lacking BRCA2 made the cells more sensitive to AG-14361 [5]. In human K562 cells, AG14361 treatment for 16 hours resulted in significant (~2-fold) potentiation of camptothecin-induced growth inhibition (GI50, 16 hours, camptothecin + AG14361 2.4 ± 0.1 nmol/L), cytotoxicity (LC50, camptothecin + AG14361 2.77 ± 0.55 nmol/L) and DNA single-strand breaks via inhibiting PARP-1 [1]. When tested with MMR-proficient (HCT-Ch3, A2780, and CP70-ch3) and MMR-deficient (HCT116, CP70, and CP70-ch2) cells, MMR-proficient cells were more sensitivity to temozolomide compared with MMR-deficient cells after exposed to AG-14361 which inhibited PARP1 activity [2].
In mouse model xenografted with BRCA2-deficient and BRCA-2 proficient tumor cells, BRCA2 deficiency group had more response even completely regressed tumor compared with BRCA-2 proficient group when treated with AG-14361 [5].
References:
[1].? Smith, L.M., et al., The novel poly(ADP-Ribose) polymerase inhibitor, AG14361, sensitizes cells to topoisomerase I poisons by increasing the persistence of DNA strand breaks. Clin Cancer Res, 2005. 11(23): p. 8449-57.
[2].? Curtin, N.J., et al., Novel poly(ADP-ribose) polymerase-1 inhibitor, AG14361, restores sensitivity to temozolomide in mismatch repair-deficient cells. Clin Cancer Res, 2004. 10(3): p. 881-9.
[3].? Calabrese, C.R., et al., Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. J Natl Cancer Inst, 2004. 96(1): p. 56-67.
[4].? Veuger, S.J., et al., Radiosensitization and DNA repair inhibition by the combined use of novel inhibitors of DNA-dependent protein kinase and poly(ADP-ribose) polymerase-1. Cancer Res, 2003. 63(18): p. 6008-15.
[5].? Kyle, S., et al., Exploiting the Achilles heel of cancer: the therapeutic potential of poly(ADP-ribose) polymerase inhibitors in BRCA2-defective cancer. Br J Radiol, 2008. 81 Spec No 1: p. S6-11.
- 1. Megha Jhanji, Chintada Nageswara Rao, et al. "Cis-and trans-resveratrol have opposite effects on histone serine-ADP-ribosylation and tyrosine induced neurodegeneration." Nat Commun. 2022 Jun 10;13(1):3244. PMID: 35688816
- 2. Soni H, Kaminski D, et al. "Cisplatin-induced oxidative stress stimulates renal Fas ligand shedding." Ren Fail. 2018 Nov;40(1):314-322. PMID: 29619879
| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 320.39 |
| Cas No. | 328543-09-5 |
| Formula | C19H20N4O |
| Solubility | insoluble in H2O; ≥10.14 mg/mL in EtOH with gentle warming and ultrasonic; ≥16 mg/mL in DMSO |
| Chemical Name | 1-(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)-one |
| SDF | Download SDF |
| Canonical SMILES | O=C1N([H])C([H])([H])C([H])([H])N2C3=C1C([H])=C([H])C([H])=C3N=C2C(C([H])=C4[H])=C([H])C([H])=C4C([H])([H])N(C([H])([H])[H])C([H])([H])[H] |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Cell experiment [1]: | |
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Cell lines |
A549, LoVo, and SW620 cells |
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Preparation method |
The solubility of this compound in DMSO is > 16 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
0.4 μM, 5 d |
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Applications |
AG14361 at concentration of 0.4 μM inhibited the activity of PARP-1 by more than 85%, but it had no effect on cancer cell gene expression or growth. AG14361 increased the antiproliferative effects of topotecan and temozolomide, inhibited LoVo cells recovering from γ-radiation damage. |
| Animal experiment [2]: | |
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Animal models |
6-8 weeks old female nude mice |
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Dosage form |
30 mg/kg, intraperitoneal administration |
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Application |
Mice were treated with AG14361 a day before implantation of ES cells and continuing for 9 days. The formation of BRCA1-/- ES derived tumors reduced by 90% comparing to control group, but the formation of BRCA1+/+ ES tumors reduced only 22%. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. Calabrese C R, Almassy R, Barton S, et al. Anticancer chemosensitization and radiosensitization by the novel poly (ADP-ribose) polymerase-1 inhibitor AG14361[J]. Journal of the National Cancer Institute, 2004, 96(1): 56-67. [2]. De Soto J A, Wang X, Tominaga Y, et al. The inhibition and treatment of breast cancer with poly (ADP-ribose) polymerase (PARP-1) inhibitors[J]. Int J Biol Sci, 2006, 2(4): 179-185. |
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| AG14361 is a potent inhibitor of PARP1 with Ki of <5 nM. | ||||||
| Targets | PARP1 | |||||
| IC50 | < 5 nM (Ki) | |||||
Quality Control & MSDS
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Chemical structure
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