ArticleMolecular cancer therapeutics2020
The Indenoisoquinoline LMP517: A Novel Antitumor Agent Targeting both TOP1 and TOP2.
Article in Molecular cancer therapeutics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 15 citations in OpenAlex.
- A Difluorinated Derivative of ARC-111 Suppresses Intrahepatic Cholangiocarcinoma Growth via Targeting Topoisomerase I.ACS pharmacology & translational science · 2025Article
- Phase 1 studies of the indenoisoquinolines LMP776 and LMP744 in patients with solid tumors and lymphomas.Cancer chemotherapy and pharmacology · 2025Article
- Design, Synthesis, and Investigation of the Pharmacokinetics and Anticancer Activities of Indenoisoquinoline Derivatives That Stabilize the G-Quadruplex in theJournal of medicinal chemistry · 2024Article
- Isolation and detection of DNA-protein crosslinks in mammalian cells.Nucleic acids research · 2024Article
- Molecular cloning, subcellular localization, and rapid recruitment to DNA damage sites of chicken Ku70.Scientific reports · 2024Article
- Synthesis and Biological Activity of a New Indenoisoquinoline Copper Derivative as a Topoisomerase I Inhibitor.International journal of molecular sciences · 2023Article
- Precursor-Directed Synthesis of Apoptosis-Initiating N-Hydroxyalkyl Phenylbenzoisoquinolindione Alkaloids.ChemistryOpen · 2022Article
- A Novel Copper(II) Indenoisoquinoline Complex Inhibits Topoisomerase I, Induces G2 Phase Arrest, and Autophagy in Three Adenocarcinomas.Frontiers in oncology · 2022Article
- Design, Synthesis and Anticancer Evaluation of Substituted Cinnamic Acid Bearing 2-Quinolone Hybrid Derivatives.Molecules (Basel, Switzerland) · 2021Article
- LncSEA: a platform for long non-coding RNA related sets and enrichment analysis.Nucleic acids research · 2021Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
The camptothecin derivatives topoisomerase I (TOP1) inhibitors, irinotecan and topotecan, are FDA approved for the treatment of colorectal, ovarian, lung and breast cancers. Because of the chemical instability of camptothecins, short plasma half-life, drug efflux by the multidrug-resistance ABC transporters, and the severe diarrhea produced by irinotecan, indenoisoquinoline TOP1 inhibitors (LMP400, LMP776, and LMP744), which overcome these limitations, have been developed and are in clinical development. Further modifications of the indenoisoquinolines led to the fluoroindenoisoquinolines, one of which, LMP517, is the focus of this study. LMP517 showed better antitumor activity than its parent compound LMP744 against H82 (small cell lung cancer) xenografts. Genetic analyses in DT40 cells showed a dual TOP1 and TOP2 signature with selectivity of LMP517 for DNA repair-deficient tyrosyl DNA phosphodiesterase 2 (TDP2)- and Ku70-knockout cells. RADAR assays revealed that LMP517, and to a lesser extent LMP744, induce TOP2 cleavage complexes (TOP2cc) in addition to TOP1ccs. Histone γH2AX detection showed that, unlike classical TOP1 inhibitors, LMP517 targets cells independently of their position in the cell cycle. Our study establishes LMP517 as a dual TOP1 and TOP2 inhibitor with therapeutic potential.
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