4g0w Citations

On the structural basis and design guidelines for type II topoisomerase-targeting anticancer drugs.

OpenAccess logo Nucleic Acids Res. (2013)
Related entries: 4j3n, 4g0u, 4g0v

Cited: 24 times
EuropePMC logo PMID: 24038465

Abstract

Type II topoisomerases (Top2s) alter DNA topology via the formation of an enzyme-DNA adduct termed cleavage complex, which harbors a transient double-strand break in one DNA to allow the passage of another. Agents targeting human Top2s are clinically active anticancer drugs whose trapping of Top2-mediated DNA breakage effectively induces genome fragmentation and cell death. To understand the structural basis of this drug action, we previously determined the structure of human Top2 β-isoform forming a cleavage complex with the drug etoposide and DNA, and described the insertion of drug into DNA cleavage site and drug-induced decoupling of catalytic groups. By developing a post-crystallization drug replacement procedure that simplifies structural characterization of drug-stabilized cleavage complexes, we have extended the analysis toward other structurally distinct drugs, m-AMSA and mitoxantrone. Besides the expected drug intercalation, a switch in ribose puckering in the 3'-nucleotide of the cleavage site was robustly observed in the new structures, representing a new mechanism for trapping the Top2 cleavage complex. Analysis of drug-binding modes and the conformational landscapes of the drug-binding pockets provide rationalization of the drugs' structural-activity relationships and explain why Top2 mutants exhibit differential effects toward each drug. Drug design guidelines were proposed to facilitate the development of isoform-specific Top2-targeting anticancer agents.

Reviews citing this publication (8)

  1. Review structure- and dynamics-based computational design of anticancer drugs. Lin JH. Biopolymers 105 2-9 (2016)
  2. Interfacial inhibitors. Pommier Y, Kiselev E, Marchand C. Bioorg. Med. Chem. Lett. 25 3961-3965 (2015)
  3. A "Double-Edged" Scaffold: Antitumor Power within the Antibacterial Quinolone. Bisacchi GS, Hale MR. Curr. Med. Chem. 23 520-577 (2016)
  4. Anthraquinones As Pharmacological Tools and Drugs. Malik EM, Müller CE. Med Res Rev 36 705-748 (2016)
  5. Review structure- and dynamics-based computational design of anticancer drugs. Lin JH. Biopolymers 105 2-9 (2016)
  6. Anthraquinones As Pharmacological Tools and Drugs. Malik EM, Müller CE. Med Res Rev 36 705-748 (2016)
  7. A "Double-Edged" Scaffold: Antitumor Power within the Antibacterial Quinolone. Bisacchi GS, Hale MR. Curr. Med. Chem. 23 520-577 (2016)
  8. Interfacial inhibitors. Pommier Y, Kiselev E, Marchand C. Bioorg. Med. Chem. Lett. 25 3961-3965 (2015)

Articles citing this publication (16)

  1. Structure-based design, synthesis and biological testing of etoposide analog epipodophyllotoxin-N-mustard hybrid compounds designed to covalently bind to topoisomerase II and DNA. Yadav AA, Wu X, Patel D, Yalowich JC, Hasinoff BB. Bioorg. Med. Chem. 22 5935-5949 (2014)
  2. Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin. Chan PF, Srikannathasan V, Huang J, Cui H, Fosberry AP, Gu M, Hann MM, Hibbs M, Homes P, Ingraham K, Pizzollo J, Shen C, Shillings AJ, Spitzfaden CE, Tanner R, Theobald AJ, Stavenger RA, Bax BD, Gwynn MN. Nat Commun 6 10048 (2015)
  3. Fitness profiling links topoisomerase II regulation of centromeric integrity to doxorubicin resistance in fission yeast. Nguyen TT, Lim JS, Tang RM, Zhang L, Chen ES. Sci Rep 5 8400 (2015)
  4. Mechanisms of Action and Reduced Cardiotoxicity of Pixantrone; a Topoisomerase II Targeting Agent with Cellular Selectivity for the Topoisomerase IIα Isoform. Hasinoff BB, Wu X, Patel D, Kanagasabai R, Karmahapatra S, Yalowich JC. J. Pharmacol. Exp. Ther. 356 397-409 (2016)
  5. pH sensitive nano layered double hydroxides reduce the hematotoxicity and enhance the anticancer efficacy of etoposide on non-small cell lung cancer. Zhu R, Wang Q, Zhu Y, Wang Z, Zhang H, Wu B, Wu X, Wang S. Acta Biomater 29 320-332 (2016)
  6. Stereoselective synthesis of 11-phenylundeca-5Z,9Z-dienoic acid and investigation of its human topoisomerase I and IIα inhibitory activity. D'yakonov VA, Dzhemileva LU, Makarov AA, Mulukova AR, Baev DS, Khusnutdinova EK, Tolstikova TG, Dzhemilev UM. Bioorg. Med. Chem. Lett. 25 2405-2408 (2015)
  7. Novel ametantrone-amsacrine related hybrids as topoisomerase IIβ poisons and cytotoxic agents. Zagotto G, Gianoncelli A, Sissi C, Marzano C, Gandin V, Pasquale R, Capranico G, Ribaudo G, Palumbo M. Arch. Pharm. (Weinheim) 347 728-737 (2014)
  8. Recovery of the poisoned topoisomerase II for DNA religation: coordinated motion of the cleavage core revealed with the microsecond atomistic simulation. Huang NL, Lin JH. Nucleic Acids Res. 43 6772-6786 (2015)
  9. Structure-based design, synthesis and biological testing of piperazine-linked bis-epipodophyllotoxin etoposide analogs. Yadav AA, Chee GL, Wu X, Patel D, Yalowich JC, Hasinoff BB. Bioorg. Med. Chem. 23 3542-3551 (2015)
  10. Novel DNA topoisomerase IIα inhibitors from combined ligand- and structure-based virtual screening. Drwal MN, Marinello J, Manzo SG, Wakelin LP, Capranico G, Griffith R. PLoS ONE 9 e114904 (2014)
  11. Preparation, characterization and evaluation of (186) Re-idarubicin: a novel agent for diagnosis and treatment of hepatocellular carcinoma. El-Kawy OA, Talaat HM. J Labelled Comp Radiopharm 59 72-77 (2016)
  12. An optimized polyamine moiety boosts the potency of human type II topoisomerase poisons as quantified by comparative analysis centered on the clinical candidate F14512. Palermo G, Minniti E, Greco ML, Riccardi L, Simoni E, Convertino M, Marchetti C, Rosini M, Sissi C, Minarini A, De Vivo M. Chem. Commun. (Camb.) 51 14310-14313 (2015)
  13. Exploring the Effects of Glycosylation and Etherification of the Side Chains of the Anticancer Drug Mitoxantrone. Shaul P, Steinbuch KB, Blacher E, Stein R, Fridman M. ChemMedChem 10 1528-1538 (2015)
  14. Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2. Hornyak P, Askwith T, Walker S, Komulainen E, Paradowski M, Pennicott LE, Bartlett EJ, Brissett NC, Raoof A, Watson M, Jordan AM, Ogilvie DJ, Ward SE, Atack JR, Pearl LH, Caldecott KW, Oliver AW. Biochem. J. 473 1869-1879 (2016)
  15. Phenanthriplatin Acts As a Covalent Poison of Topoisomerase II Cleavage Complexes. Riddell IA, Agama K, Park GY, Pommier Y, Lippard SJ. ACS Chem. Biol. 11 2996-3001 (2016)
  16. Roles of the C-terminal domains of topoisomerase IIα and topoisomerase IIβ in regulation of the decatenation checkpoint. Kozuki T, Chikamori K, Surleac MD, Micluta MA, Petrescu AJ, Norris EJ, Elson P, Hoeltge GA, Grabowski DR, Porter ACG, Ganapathi RN, Ganapathi MK. Nucleic Acids Res. 45 5995-6010 (2017)