May 21, 2020

The indenoisoquinoline LMP517: a novel antitumor agent targeting both TOP1 and TOP2

Molecular Cancer Therapeutics
Laetitia MarziYves Pommier


The camptothecin derivatives topoisomerase I (TOP1) inhibitors, irinotecan and topotecan are US-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 the present 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 (TOP2ccs) 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 es...Continue Reading

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Mentioned in this Paper

Topoisomerase I Inhibitor LMP400
Drug Efflux
Membrane Transport Proteins
Malignant Neoplasm of Breast
Antineoplastic Agents
Xenograft Type of Graft

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