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).¹ 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/β-catenin signaling pathway proteins axin2, total and active β-catenin, and cyclin D1 in SW480 cells. In vivo, E7449 enhances tumor growth inhibition induced by temozolomide (TMZ; Item No. 14163) in a B16/F10 isograft model as well as antitumor activity of the DNA-crosslinking agent carboplatin (Item No. 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.

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1. McGonigle, S., Chen, Z., Wu, J., et al. E7449: A dual inhibitor of PARP1/2 and tankyrase1/2 inhibits growth of DNA repair deficient tumors and antagonizes Wnt signaling. Oncotarget 6(38), 41307-41323 (2015).