title: 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.
authors.affiliation: Discovery Biology, Oncology PCU, Eisai Inc., Andover, MA 01810, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: McGonigle
authors.affiliation: Discovery Biology, Oncology PCU, Eisai Inc., Andover, MA 01810, USA.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Discovery Biology, Oncology PCU, Eisai Inc., Andover, MA 01810, USA.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.|Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Chang
authors.affiliation: Discovery Biology, Oncology PCU, Eisai Inc., Andover, MA 01810, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Kolber-Simonds
authors.affiliation: Discovery Biology, Oncology PCU, Eisai Inc., Andover, MA 01810, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Ackermann
authors.affiliation: Discovery Biology, Oncology PCU, Eisai Inc., Andover, MA 01810, USA.
authors.forename: Natalie C
authors.initials: NC
authors.lastname: Twine
authors.affiliation: Discovery Biology, Oncology PCU, Eisai Inc., Andover, MA 01810, USA.
authors.forename: Jue-Lon
authors.initials: JL
authors.lastname: Shie
authors.affiliation: Discovery Biology, Oncology PCU, Eisai Inc., Andover, MA 01810, USA.|Current address: Moderna Therapeutics, Cambridge, MA 02139, USA.
authors.forename: Jingzang Tao
authors.initials: JT
authors.lastname: Miu
authors.affiliation: Discovery Biology, Oncology PCU, Eisai Inc., Andover, MA 01810, USA.
authors.forename: Kuan-Chun
authors.initials: KC
authors.lastname: Huang
authors.affiliation: Integrated Chemistry, Eisai Inc., Andover, MA 01810, USA.|Current address: Biogen, Cambridge, MA 02142, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: Moniz
authors.affiliation: Discovery Biology, Oncology PCU, Eisai Inc., Andover, MA 01810, USA.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nomoto
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001391:Azo Compounds; D015153:Blotting, Western; D016190:Carboplatin / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D052999:Quinazolinones / Q000737:chemistry / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D038501:Tankyrases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000077204:Temozolomide; D047368:Tumor Burden / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D001391:Azo Compounds; D016190:Carboplatin; D004268:DNA-Binding Proteins; D003606:Dacarbazine; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D052999:Quinazolinones; D038501:Tankyrases; D000077204:Temozolomide; C556015:PARPBP protein, human; C000611123:stenoparib; C483041:PARP2 protein, human; C437334:TNKS2 protein, human; C418109:TNKS protein, human
keywords: E7449; PARP; Wnt; inhibitor; tankyrase