AG14361

• CAT Number: I003166
• CAS Number: 328543-09-5
• Molecular Formula: C19H20N4O
• Molecular Weight: 320.39
• Purity: ≥95%
• Synonyms: 1-(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen-6(7H)-one
• Target: PARP
• Solubility: DMSO: ≥ 32 mg/mL
• Storage: 3 years -20C powder
• IC50: <5 nM( Ki)
• InChI: InChI=1S/C19H20N4O/c1-22(2)12-13-6-8-14(9-7-13)18-21-16-5-3-4-15-17(16)23(18)11-10-20-19(15)24/h3-9H,10-12H2,1-2H3,(H,20,24)
• InChIKey: SEKJSSBJKFLZIT-UHFFFAOYSA-N
• SMILES: O=C1C2=C3C(N=C(C4=CC=C(CN(C)C)C=C4)N3CCN1)=CC=C2

AG14361 is a potent inhibitor of PARP1 with Ki of <5 nM. It is at least 1000-fold more potent than the benzamides.IC50 Value: <5 nM( Ki)Target: PARP1in vitro: AG14361 is at least 1000-fold more potent than the benzamides. The IC50 for AG14361 is 29 nM in permeabilized SW620 cells and 14 nM in intact SW620 cells. Crystallographic analysis of AG14361 bound to the catalytic domain of chicken PARP-1 shows that the tricyclic ring system of AG14361 is located in a pocket composed of amino acid residues Trp861, His862, Gly863, Tyr896, Phe897, Ala898, Lys903, Ser904, Tyr907, and Glu988. AG14361 forms important hydrogen bonds with Ser904 and Gly863 and a water-mediated hydrogen bond with Glu988. AG14361-induced growth inhibition is not attributed to PARP-1-related effects because maximal PARP-1 inhibition is observed at much lower concentrations (≤1 μM) than the GI50. AG14361 at 0.4 μM does not affect cancer cell gene expression or growth, but it increases the antiproliferative activity of temozolomide and topotecan, and inhibits recovery from potentially lethal γ-radiation damage in LoVo cells by 73%. In addition, 0.4 μM AG14361 does not substantially alter gene expression as shown by microarray analysis. A 17-hour exposure of A549 cells to 0.4 μM AG14361 does not change the expression of the 6800 genes.in vivo: AG14361 treatment before irradiation statistically significantly increases the sensitivity to radiation therapy of mice bearing LoVo xenografts. AG14361 statistically significantly increases blood flow in xenografts and thus potentially increases drug delivery to tumor xenografts. In vivo, nontoxic doses of AG14361 increases the delay of LoVo xenograft growth induced by irinotecan, x-irradiation, or temozolomide by 2- to 3-fold. Coadministration of AG14361 with temozolomide statistically significantly increases temozolomide activity against LoVo xenografts, with the tumor growth delay being increased from 3 days to 9 days by AG14361 at 5 mg/kg and to 10 days by AG14361 at 15 mg/kg. The combination of AG14361 and temozolomide causes complete regression of SW620 xenograft tumors. PARP-1 activity, detected by pharmacodynamic assay, in SW620 xenografts is inhibited by more than 75% for at least 4 hours after intraperitoneal administration of AG14361 (10 mg/kg), consistent with the concentration of AG14361 persisting in the tumor.

Reference

1:Drug repurposing screen identifies lestaurtinib amplifies the ability of the poly (ADP-ribose) polymerase 1 inhibitor AG14361 to kill breast cancer associated gene-1 mutant and wild type breast cancer cells. Vazquez-Ortiz G, Chisholm C, Xu X, Lahusen TJ, Li C, Sakamuru S, Huang R, Thomas CJ, Xia M, Deng C.Breast Cancer Res. 2014 Jun 24;16(3):R67. doi: 10.1186/bcr3682. PMID: 24962108 Free PMC Article2:The novel poly(ADP-Ribose) polymerase inhibitor, AG14361, sensitizes cells to topoisomerase I poisons by increasing the persistence of DNA strand breaks. Smith LM, Willmore E, Austin CA, Curtin NJ.Clin Cancer Res. 2005 Dec 1;11(23):8449-57. PMID: 16322308 Free Article3:Novel poly(ADP-ribose) polymerase-1 inhibitor, AG14361, restores sensitivity to temozolomide in mismatch repair-deficient cells. Curtin NJ, Wang LZ, Yiakouvaki A, Kyle S, Arris CA, Canan-Koch S, Webber SE, Durkacz BW, Calvert HA, Hostomsky Z, Newell DR.Clin Cancer Res. 2004 Feb 1;10(3):881-9. PMID: 14871963 Free Article4:Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. Calabrese CR, Almassy R, Barton S, Batey MA, Calvert AH, Canan-Koch S, Durkacz BW, Hostomsky Z, Kumpf RA, Kyle S, Li J, Maegley K, Newell DR, Notarianni E, Stratford IJ, Skalitzky D, Thomas HD, Wang LZ, Webber SE, Williams KJ, Curtin NJ.J Natl Cancer Inst. 2004 Jan 7;96(1):56-67. PMID: 14709739