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Laetitia Marzi, Keli Agama, Junko Murai, Simone Difilippantonio, Amy James, Cody J Peer, William D Figg, Daniel Beck, Mohamed S A Elsayed, Mark Cushman, Yves Pommier
Contrary to other anticancer targets, topoisomerase I (TOP1) is targeted by only one chemical class of FDA-approved drugs: topotecan and irinotecan, the derivatives of the plant alkaloid, camptothecin. The indenoisoquinolines LMP400, LMP744 and LMP776 are novel non-camptothecin TOP1 inhibitors in clinical trial, which overcome the limitations of camptothecins. To further improve metabolic stability, their methoxy groups have been replaced by a fluorine, as in the fluoroindenoisoquinolines NSC 781517 (LMP517), NSC 779135 (LMP135) and NSC 779134 (LMP134)...
May 10, 2018: Molecular Cancer Therapeutics
Shivaani Kummar, Alice Chen, Martin Gutierrez, Thomas D Pfister, Lihua Wang, Christophe Redon, William M Bonner, William Yutzy, Yiping Zhang, Robert J Kinders, Jiuping Ji, Deborah Allen, Joseph M Covey, Julie L Eiseman, Julianne L Holleran, Jan H Beumer, Larry Rubinstein, Jerry Collins, Joseph Tomaszewski, Ralph Parchment, Yves Pommier, James H Doroshow
PURPOSE: Indenoisoquinolines are non-camptothecin topoisomerase I (TopI) inhibitors that overcome the limitations of camptothecins: chemical instability and camptothecin resistance. Two dosing schedules of the novel indenoisoquinoline, indotecan (LMP400), were evaluated in patients with advanced solid tumors. METHODS: The maximum tolerated dose (MTD), toxicities, and pharmacokinetics of two indotecan drug administration schedules (daily for 5 days or weekly) were investigated...
July 2016: Cancer Chemotherapy and Pharmacology
Peng-Cheng Lv, Mohamed S A Elsayed, Keli Agama, Christophe Marchand, Yves Pommier, Mark Cushman
Indenoisoquinoline topoisomerase I (Top1) inhibitors are a novel class of anticancer agents with two compounds in clinical trials. Recent metabolism studies of indotecan (LMP400) led to the discovery of the biologically active 2-hydroxylated analogue and 3-hydroxylated metabolite, thus providing strategically placed functional groups for the preparation of a variety of potential ester prodrugs of these two compounds. The current study details the design and synthesis of two series of indenoisoquinoline prodrugs, and it also reveals how substituents on the O-2 and O-3 positions of the A ring, which are next to the cleaved DNA strand in the drug-DNA-Top1 ternary cleavage complex, affect Top1 inhibitory activity and cytotoxicity...
May 26, 2016: Journal of Medicinal Chemistry
Hee-Sheung Lee, Nicholas C O Lee, Natalay Kouprina, Jung-Hyun Kim, Alex Kagansky, Susan Bates, Jane B Trepel, Yves Pommier, Dan Sackett, Vladimir Larionov
Whole chromosomal instability (CIN), manifested as unequal chromosome distribution during cell division, is a distinguishing feature of most cancer types. CIN is generally considered to drive tumorigenesis, but a threshold level exists whereby further increases in CIN frequency in fact hinder tumor growth. While this attribute is appealing for therapeutic exploitation, drugs that increase CIN beyond this therapeutic threshold are currently limited. In our previous work, we developed a quantitative assay for measuring CIN based on the use of a nonessential human artificial chromosome (HAC) carrying a constitutively expressed EGFP transgene...
February 15, 2016: Cancer Research
Haatisha Jandu, Kristina Aluzaite, Louise Fogh, Sebastian Wingaard Thrane, Julie B Noer, Joanna Proszek, Khoa Nguyen Do, Stine Ninel Hansen, Britt Damsgaard, Signe Lykke Nielsen, Magnus Stougaard, Birgitta R Knudsen, José Moreira, Petra Hamerlik, Madhavsai Gajjar, Marcel Smid, John Martens, John Foekens, Yves Pommier, Nils Brünner, Anne-Sofie Schrohl, Jan Stenvang
BACKGROUND: Studies in taxane and/or anthracycline refractory metastatic breast cancer (mBC) patients have shown approximately 30% response rates to irinotecan. Hence, a significant number of patients will experience irinotecan-induced side effects without obtaining any benefit. The aim of this study was to lay the groundwork for development of predictive biomarkers for irinotecan treatment in BC. METHODS: We established BC cell lines with acquired or de novo resistance to SN-38, by exposing the human BC cell lines MCF-7 and MDA-MB-231 to either stepwise increasing concentrations over 6 months or an initial high dose of SN-38 (the active metabolite of irinotecan), respectively...
January 22, 2016: BMC Cancer
Daniel E Beck, Keli Agama, Christophe Marchand, Adel Chergui, Yves Pommier, Mark Cushman
Carbohydrate moieties were strategically transported from the indolocarbazole topoisomerase I (Top1) inhibitor class to the indenoisoquinoline system in search of structurally novel and potent Top1 inhibitors. The syntheses and biological evaluation of 20 new indenoisoquinolines glycosylated with linear and cyclic sugar moieties are reported. Aromatic ring substitution with 2,3-dimethoxy-8,9-methylenedioxy or 3-nitro groups exerted strong effects on antiproliferative and Top1 inhibitory activities. While the length of the carbohydrate side chain clearly correlated with antiproliferative activity, the relationship between stereochemistry and biological activity was less clearly defined...
February 27, 2014: Journal of Medicinal Chemistry
Yuko Maede, Hiroyasu Shimizu, Toru Fukushima, Toshiaki Kogame, Terukazu Nakamura, Tsuneharu Miki, Shunichi Takeda, Yves Pommier, Junko Murai
Clinical topoisomerase I (Top1) and II (Top2) inhibitors trap topoisomerases on DNA, thereby inducing protein-linked DNA breaks. Cancer cells resist the drugs by removing topoisomerase-DNA complexes, and repairing the drug-induced DNA double-strand breaks (DSB) by homologous recombination and nonhomologous end joining (NHEJ). Because numerous enzymes and cofactors are involved in the removal of the topoisomerase-DNA complexes and DSB repair, it has been challenging to comprehensively analyze the relative contribution of multiple genetic pathways in vertebrate cells...
January 2014: Molecular Cancer Therapeutics
Maris A Cinelli, P V Narasimha Reddy, Peng-Cheng Lv, Jian-Hua Liang, Lian Chen, Keli Agama, Yves Pommier, Richard B van Breemen, Mark Cushman
Hydroxylated analogues of the anticancer topoisomerase I (Top1) inhibitors indotecan (LMP400) and indimitecan (LMP776) have been prepared because (1) a variety of potent Top1 poisons are known that contain strategically placed hydroxyl groups, which provides a clear rationale for incorporating them in the present case, and (2) the hydroxylated compounds could conceivably serve as synthetic standards for the identification of metabolites. Indeed, incubating LMP400 and LMP776 with human liver microsomes resulted in two major metabolites of each drug, which had HPLC retention times and mass fragmentation patterns identical to those of the synthetic standards...
December 27, 2012: Journal of Medicinal Chemistry
Rafael Balaña-Fouce, Christopher F Prada, José María Requena, Mark Cushman, Yves Pommier, Raquel Álvarez-Velilla, José Miguel Escudero-Martínez, Estefania Calvo-Álvarez, Yolanda Pérez-Pertejo, Rosa M Reguera
Visceral leishmaniasis is an emerging neglected tropical disease (NTD) caused by the protozoan Leishmania infantum in the countries bordering the Mediterranean Basin. Currently there is no effective vaccine against this disease, and the therapeutic approach is based on toxic derivatives of Sb(V). Therefore, the discovery of new therapeutic targets and the development of drugs designed to inhibit them comprise an extremely important approach to fighting this disease. DNA topoisomerases (Top) have been identified as promising targets for therapy against leishmaniasis...
October 2012: Antimicrobial Agents and Chemotherapy
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