ArticleMolecular cancer therapeutics2011
Molecular and cellular pharmacology of the novel noncamptothecin topoisomerase I inhibitor Genz-644282.
Article in Molecular cancer therapeutics, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 38 citations in OpenAlex.
- A Difluorinated Derivative of ARC-111 Suppresses Intrahepatic Cholangiocarcinoma Growth via Targeting Topoisomerase I.ACS pharmacology & translational science · 2025Article
- Prospects of Topoisomerase Inhibitors as Promising Anti-Cancer Agents.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Article
- Payload diversification: a key step in the development of antibody-drug conjugates.Journal of hematology & oncology · 2023Review
- Article
- Mechanism of action of non-camptothecin inhibitor Genz-644282 in topoisomerase I inhibition.Communications biology · 2022Article
- The benzylisoquinoline alkaloids, berberine and coptisine, act against camptothecin-resistant topoisomerase I mutants.Scientific reports · 2021Article
- High activity and low toxicity of a novel CD71-targeting nanotherapeutic named The-0504 on preclinical models of several human aggressive tumors.Journal of experimental & clinical cancer research : CR · 2021Article
- DNA topoisomerases as molecular targets for anticancer drugs.Journal of enzyme inhibition and medicinal chemistry · 2020Review
- Engineered Human Nanoferritin Bearing the Drug Genz-644282 for Cancer Therapy.Pharmaceutics · 2020Article
- Prioritization of candidate cancer drugs based on a drug functional similarity network constructed by integrating pathway activities and drug activities.Molecular oncology · 2019Article
- Synthesis and biological evaluation of 5-aminoethyl benzophenanthridone derivatives as DNA topoisomerase IB inhibitors.European journal of medicinal chemistry · 2019Article
- Discovery, Synthesis, and Evaluation of Oxynitidine Derivatives as Dual Inhibitors of DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1), and Potential Antitumor Agents.Journal of medicinal chemistry · 2018Article
- Ascorbic Acid Chemosensitizes Colorectal Cancer Cells and Synergistically Inhibits Tumor Growth.Frontiers in physiology · 2018Article
- Camptothecin (CPT) and its derivatives are known to target topoisomerase I (Top1) as their mechanism of action: did we miss something in CPT analogue molecular targets for treating human disease such as cancer?American journal of cancer research · 2017Review
- Sophoridinol derivative 05D induces tumor cells apoptosis by topoisomerase1-mediated DNA breakage.OncoTargets and therapy · 2016Article
- Article
- Optimization of the lactam side chain of 7-azaindenoisoquinoline topoisomerase I inhibitors and mechanism of action studies in cancer cells.Journal of medicinal chemistry · 2014Article
- Drugging topoisomerases: lessons and challenges.ACS chemical biology · 2013Review
- Identification, synthesis, and biological evaluation of metabolites of the experimental cancer treatment drugs indotecan (LMP400) and indimitecan (LMP776) and investigation of isomerically hydroxylated indenoisoquinoline analogues as topoisomerase I poisons.Journal of medicinal chemistry · 2012Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Camptothecin derivatives are powerful anticancer drugs because of their ability to trap topoisomerase I (Top1)-DNA cleavage complexes. However, they exhibit clinical limitations due to the instability of their α-hydroxylactone six-membered E-ring structure. In addition, they exhibit bone marrow and intestinal toxicity, especially in adults, and are drug efflux substrates. Here, we report a novel Top1 inhibitor, Genz-644282. We show that Genz-644282 and its metabolites induce Top1 cleavage at similar, as well as unique genomic positions, compared with camptothecin. The compound also induces protein-linked DNA breaks and Top1-DNA cleavage complexes that persist longer after compound removal than camptothecin. Concentration-dependent and persistent γH2AX formation was readily observed in cells treated with Genz-644282, and was present in greater than 50% of the cell population following 24 hours compound exposure. The compound shows partial cross-resistance in cell lines resistant to camptothecin. These cell lines include the human prostate DU145RC0.1 and the leukemic CEM/C2 cells. Limited cross-resistance to Genz-644282 was also found in the Top1 knockdown colon cancer (HCT116) and breast cancer (MCF7) cell lines and in human adenocarcinoma cells (KB31/KBV1) that overexpress (P-glycoprotein, ABCB1), a member of the ATP-binding cassette family of cell surface transport proteins known to confer MDR. Together, our results provide the first molecular and cellular characterization of Genz-644282 and its clinically relevant metabolites.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.