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Ref Type Journal Article
PMID (26513298)
Authors 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
Title E7449: A dual inhibitor of PARP1/2 and tankyrase1/2 inhibits growth of DNA repair deficient tumors and antagonizes Wnt signaling.
Journal Oncotarget
Vol 6
Issue 38
Date 2015 Dec 01
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
E7449 E7449 5 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
E7449 2X-121 PARP Inhibitor (Pan) 20 Tankyrase Inhibitor 10 E7449 (2X-121) binds to and inhibits PARP1 and PARP2, as well as TNKS1 and TNKS2, potentially resulting in increased sensitivity to DNA damaging agents and decreased growth of tumor cells with defective DNA damage repair (PMID: 26513298, PMID: 32523090).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ATRX inact mut Advanced Solid Tumor sensitive E7449 Preclinical Actionable In a preclinical study, E7449 inhibited proliferation of a ATRX-deficient cell line in culture, which demonstrated increased sensitivity compared to cells without DNA repair pathway mutations (PMID: 26513298). 26513298
Unknown unknown breast cancer not applicable Carboplatin + E7449 Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of E7449 and Paraplatin (carboplatin) synergized to inhibit tumor growth in a human breast cancer cell line xenograft model (PMID: 26513298). 26513298
ATM inact mut Advanced Solid Tumor sensitive E7449 Preclinical Actionable In a preclinical study, E7449 inhibited proliferation of a ATM-deficient cell line in culture, which demonstrated increased sensitivity compared to cells without DNA repair pathway mutations (PMID: 26513298). 26513298
Unknown unknown melanoma not applicable E7449 + Temozolomide Preclinical Actionable In a preclinical study, the combination of E7449 and Temodar (temozolomide) inhibited tumor growth in mouse melanoma models, with increased efficacy compared to either agent alone (PMID: 26513298). 26513298