Inhibition of Poly(ADP-ribose) Polymerase1 (PARP1) impairs DNA damage repair, 
and early generation PARP1/2 inhibitors (olaparib, niraparib, etc.) have 
demonstrated clinical proof of concept for cancer treatment. Here, we describe 
the development of the novel PARP inhibitor E7449, a potent PARP1/2 inhibitor 
that also inhibits PARP5a/5b, otherwise known as tankyrase1 and 2 (TNKS1 and 2), 
important regulators of canonical Wnt/β-catenin signaling. E7449 inhibits PARP 
enzymatic activity and additionally traps PARP1 onto damaged DNA; a mechanism 
previously shown to augment cytotoxicity. Cells deficient in DNA repair pathways 
beyond homologous recombination were sensitive to E7449 treatment. Chemotherapy 
was potentiated by E7449 and single agent had significant antitumor activity in 
BRCA-deficient xenografts. Additionally, E7449 inhibited Wnt/β-catenin signaling 
in colon cancer cell lines, likely through TNKS inhibition. Consistent with this 
possibility, E7449 stabilized axin and TNKS proteins resulting in β-catenin 
de-stabilization and significantly altered expression of Wnt target genes. 
Notably, hair growth mediated by Wnt signaling was inhibited by E7449. A 
pharmacodynamic effect of E7449 on Wnt target genes was observed in tumors, 
although E7449 lacked single agent antitumor activity in vivo, a finding typical 
for selective TNKS inhibitors. E7449 antitumor activity was increased through 
combination with MEK inhibition. Particularly noteworthy was the lack of 
toxicity, most significantly the lack of intestinal toxicity reported for other 
TNKS inhibitors. E7449 represents a novel dual PARP1/2 and TNKS1/2 inhibitor 
which has the advantage of targeting Wnt/β-catenin signaling addicted tumors. 
E7449 is currently in early clinical development.