E7449: A dual inhibitor of PARP1/2 and tankyrase1/2 inhibits growth of DNA repair deficient tumors and antagonizes Wnt signaling
| Autor: | Kenichi Nomoto, Kuan-Chun Huang, Donna Kolber-Simonds, Natalie C. Twine, George A. Moniz, Paul Chang, Jue-lon Shie, Jingzang Tao Miu, Karen Ackermann, Zhihong Chen, Sharon McGonigle, Jiayi Wu |
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| Přispěvatelé: | Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Chang, Paul |
| Rok vydání: | 2015 |
| Předmět: |
DNA Repair
DNA repair Poly ADP ribose polymerase Blotting Western Mice Nude Mice SCID Poly(ADP-ribose) Polymerase Inhibitors Biology Bioinformatics tankyrase Poly (ADP-Ribose) Polymerase Inhibitor Carboplatin PARP Olaparib Wnt chemistry.chemical_compound PARP1 Cell Line Tumor Neoplasms Antineoplastic Combined Chemotherapy Protocols Temozolomide Animals Wnt Signaling Pathway Cell Proliferation Quinazolinones Tankyrases Reverse Transcriptase Polymerase Chain Reaction Cell growth Gene Expression Profiling Wnt signaling pathway Neoplasms Experimental E7449 Isoquinolines Xenograft Model Antitumor Assays Tumor Burden DNA-Binding Proteins Dacarbazine Gene Expression Regulation Neoplastic Mice Inbred C57BL inhibitor Oncology chemistry PARP inhibitor Cancer research Female Poly(ADP-ribose) Polymerases Azo Compounds Research Paper |
| Zdroj: | Oncotarget Impact Journals/National Center for Biotechnology Information (U.S.) |
| ISSN: | 1949-2553 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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