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E7449: A dual inhibitor of PARP1/2 and tankyrase1/2 inhibits growth of DNA repair
deficient tumors and antagonizes Wnt signaling
#MMPMID26513298
McGonigle S
; Chen Z
; Wu J
; Chang P
; Kolber-Simonds D
; Ackermann K
; Twine NC
; Shie JL
; Miu JT
; Huang KC
; Moniz GA
; Nomoto K
Oncotarget
2015[Dec]; 6
(38
): 41307-23
PMID26513298
show ga
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/?-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/?-catenin signaling
in colon cancer cell lines, likely through TNKS inhibition. Consistent with this
possibility, E7449 stabilized axin and TNKS proteins resulting in ?-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/?-catenin signaling addicted tumors.
E7449 is currently in early clinical development.
free
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