Oncotarget

Research Papers:

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

Sharon McGonigle _, Zhihong Chen, Jiayi Wu, Paul Chang, Donna Kolber-Simonds, Karen Ackermann, Natalie C. Twine, Jue-lon Shie, Jingzang Tao Miu, Kuan-Chun Huang, George A. Moniz and Kenichi Nomoto

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Oncotarget. 2015; 6:41307-41323. https://doi.org/10.18632/oncotarget.5846

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Abstract

Sharon McGonigle1,*, Zhihong Chen1,*, Jiayi Wu1, Paul Chang3,4, Donna Kolber-Simonds1, Karen Ackermann1, Natalie C. Twine1, Jue-Lon Shie1,§, Jingzang Tao Miu1,5, Kuan-Chun Huang1, George A. Moniz2,6, Kenichi Nomoto1

1Discovery Biology, Oncology PCU, Eisai Inc., Andover, MA 01810, USA

2Integrated Chemistry, Eisai Inc., Andover, MA 01810, USA

3Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

4Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

5Current address: Moderna Therapeutics, Cambridge, MA 02139, USA

6Current address: Biogen, Cambridge, MA 02142, USA

*These authors have contributed equally to this work

§This manuscript is dedicated to the memory of our friend and colleague Jue-Lon Shie, RIP

Correspondence to:

Sharon McGonigle, e-mail: sharon_mcgonigle@eisai.com

Keywords: E7449, PARP, tankyrase, inhibitor, Wnt

Received: September 14, 2015     Accepted: September 22, 2015     Published: October 20, 2015

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.


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