E7449: A dual inhibitor of PARP1/2 and tankyrase1/2 inhibits growth of DNA repair deficient tumors and antagonizes Wnt signaling

Abstract

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.

TNFR2 promotes Adriamycin resistance in breast cancer cells by repairing DNA damage

“…MGMT and PARP are both important DNA repair proteases (28,29). To test whether TNFR2 could repair DNA damage by regulating DNA repair proteins, we examined the expression levels of MGMT and PARP.…”

Rnf25/AO7 positively regulates wnt signaling via disrupting Nkd1-Axin inhibitory complex independent of its ubiquitin ligase activity

“…We have also verified the Nkd1-Axin, Rnf25-Nkd1 and Rnf25-Axin interaction via co-IP and GST pull-down, and postulated the existence of an Rnf25-Axin-Nkd1 ternary complex by two-step co-IP. As previous reviewed, Axin has been well established as a scaffold protein for multiple signaling pathways by a broad range of mechanisms [ 23 ]. The identification of Rnf25 as a novel Axin-interactor strengthened the idea that Axin is a key scaffold supporting multiple components in JNK, p53, TGFb, and Wnt.…”

Objective, Quantitative, Data-Driven Assessment of Chemical Probes

“…From the five pan-PARP probes recommended by the Chemical Probes Portal, olaparib, veliparib and niraparib are highly ranked by our predefined Global Score (Figure 3 and 4). Unfortunately, key information is missing in public resources regarding the probes AZ0108 and E7449, the latter published in a journal not indexed in public databases (20). Accordingly, these two probes are not highly ranked in our resource ( Figure 4).…”