E7449

E7449 is an inhibitor of poly(ADP-ribose) polymerase 1 (PARP1) and PARP2 (IC50s = 1 and 1.2 nM, respectively) as well as tankyrase (TNKS) 1/2 (IC50s = 50-100 nM). It is selective for PARP1, PARP2, and TNKS1/2 over PARP3 and PARP6-15 (IC50s = >3 µM). E7449 binds to chromatin in a concentration-dependent manner and inhibits growth of DT40 cells in a PARP-dependent manner (IC50s = 3.2 and >15 µM for wild-type and PARP-/- cells, respectively). It also decreases expression of the Wnt/beta-catenin signaling pathway proteins axin2, total and active beta-catenin, and cyclin D1 in SW480 cells. In vivo, E7449 enhances tumor growth inhibition induced by temozolomide (TMZ, Cay-14163) in a B16/F10 isograft model as well as antitumor activity of the DNA-crosslinking agent carboplatin (Cay-13112) in an MX-1 mouse xenograft model. E7449 (30 and 100 mg/kg per day) inhibits tumor growth in a BRCA1 mutant MDA-MB-436 breast cancer mouse xenograft model and induces complete inhibition of tumor cell PARP activity in an NCI-H460 lung cancer mouse xenograft model when administered at a dose of 100 mg/kg. It also delays hair regrowth, a TNKS-dependent process, in mice following hair removal.Formal Name: 8-[(1,3-dihydro-2H-isoindol-2-yl)methyl]-1,2-dihydro-3H-pyridazino[3,4,5-de]quinazolin-3-one. CAS Number: 1140964-99-3. Molecular Formula: C18H15N5O. Formula Weight: 317.3. Purity: >98%. Formulation: (Request formulation change), A crystalline solid. Solubility: DMF: 0.2 mg/ml, DMSO: 0.2 mg/ml, DMSO:PBS(pH 7.2) (1:2): 0.2 mg/ml. lambdamax: 207, 310 nm. SMILES: O=C1C2=CC=CC3=C2C(N=C(CN4CC(C=CC=C5)=C5C4)N3)=NN1. InChi Code: InChI=1S/C18H15N5O/c24-18-13-6-3-7-14-16(13)17(21-22-18)20-15(19-14)10-23-8-11-4-1-2-5-12(11)9-23/h1-7H,8-10H2,(H,22,24)(H,19,20,21). InChi Key: JLFSBHQQXIAQEC-UHFFFAOYSA-N.