2gm1 › Citations

Synthesis and SAR of pyrrolotriazine-4-one based Eg5 inhibitors.

Kim KS, Lu S, Cornelius LA, Lombardo LJ, Borzilleri RM, Schroeder GM, Sheng C, Rovnyak G, Crews D, Schmidt RJ, Williams DK, Bhide RS, Traeger SC, McDonnell PA, Mueller L, Sheriff S, Newitt JA, Pudzianowski AT, Yang Z, Wild R, Lee FY, Batorsky R, Ryder JS, Ortega-Nanos M, Shen H, Gottardis M, Roussell DL
Bioorg Med Chem Lett 16 3937-42 (2006)
Cited: 27 times
EuropePMC logo PMID: 16730979

Abstract

Synthesis and SAR of substituted pyrrolotriazine-4-one analogues as Eg5 inhibitors are described. Many of these analogues displayed potent inhibitory activities in the Eg5 ATPase and A2780 cell proliferation assays. In addition, pyrrolotriazine-4-one analogue 26 demonstrated in vivo efficacy in an iv P388 murine leukemia model. Both NMR and X-ray crystallographic studies revealed that these analogues bind to an allosteric site on the Eg5 protein.

Articles - 2gm1 mentioned but not cited (2)

  1. Electrostatically biased binding of kinesin to microtubules. Grant BJ, Gheorghe DM, Zheng W, Alonso M, Huber G, Dlugosz M, McCammon JA, Cross RA. PLoS Biol 9 e1001207 (2011)
  2. The structure of the ternary Eg5-ADP-ispinesib complex. Talapatra SK, Schüttelkopf AW, Kozielski F. Acta Crystallogr D Biol Crystallogr 68 1311-1319 (2012)


Reviews citing this publication (3)

  1. Kinesins and cancer. Rath O, Kozielski F. Nat Rev Cancer 12 527-539 (2012)
  2. Pyrrolo[2,1-f][1,2,4]triazine: a promising fused heterocycle to target kinases in cancer therapy. Singh S, Utreja D, Kumar V. Med Chem Res 31 1-25 (2022)
  3. Pyrrolotriazinone as an Underexplored Scaffold in Drug Discovery. Ge T, Cintrat JC. Pharmaceuticals (Basel) 14 1275 (2021)

Articles citing this publication (22)

  1. Druggability Assessment of Allosteric Proteins by Dynamics Simulations in the Presence of Probe Molecules. Bakan A, Nevins N, Lakdawala AS, Bahar I. J Chem Theory Comput 8 2435-2447 (2012)
  2. Dimeric Eg5 maintains processivity through alternating-site catalysis with rate-limiting ATP hydrolysis. Krzysiak TC, Gilbert SP. J Biol Chem 281 39444-39454 (2006)
  3. Structure of human Eg5 in complex with a new monastrol-based inhibitor bound in the R configuration. Garcia-Saez I, DeBonis S, Lopez R, Trucco F, Rousseau B, Thuéry P, Kozielski F. J Biol Chem 282 9740-9747 (2007)
  4. Discovery and biochemical characterization of selective ATP competitive inhibitors of the human mitotic kinesin KSP. Rickert KW, Schaber M, Torrent M, Neilson LA, Tasber ES, Garbaccio R, Coleman PJ, Harvey D, Zhang Y, Yang Y, Marshall G, Lee L, Walsh ES, Hamilton K, Buser CA. Arch Biochem Biophys 469 220-231 (2008)
  5. The conserved L5 loop establishes the pre-powerstroke conformation of the Kinesin-5 motor, eg5. Larson AG, Naber N, Cooke R, Pate E, Rice SE. Biophys J 98 2619-2627 (2010)
  6. The discovery and optimization of hexahydro-2H-pyrano[3,2-c]quinolines (HHPQs) as potent and selective inhibitors of the mitotic kinesin-5. Schiemann K, Finsinger D, Zenke F, Amendt C, Knöchel T, Bruge D, Buchstaller HP, Emde U, Stähle W, Anzali S. Bioorg Med Chem Lett 20 1491-1495 (2010)
  7. Synthesis and SAR of thiophene containing kinesin spindle protein (KSP) inhibitors. Pinkerton AB, Lee TT, Hoffman TZ, Wang Y, Kahraman M, Cook TG, Severance D, Gahman TC, Noble SA, Shiau AK, Davis RL. Bioorg Med Chem Lett 17 3562-3569 (2007)
  8. NSC 622124 inhibits human Eg5 and other kinesins via interaction with the conserved microtubule-binding site. Learman SS, Kim CD, Stevens NS, Kim S, Wojcik EJ, Walker RA. Biochemistry 48 1754-1762 (2009)
  9. Pharmacophore identification of KSP inhibitors. Liu F, You QD, Chen YD. Bioorg Med Chem Lett 17 722-726 (2007)
  10. Structural dynamics of the microtubule binding and regulatory elements in the kinesin-like calmodulin binding protein. Vinogradova MV, Malanina GG, Reddy VS, Reddy AS, Fletterick RJ. J Struct Biol 163 76-83 (2008)
  11. Assessing compound binding to the Eg5 motor domain using a thermal shift assay. McDonnell PA, Yanchunas J, Newitt JA, Tao L, Kiefer SE, Ortega M, Kut S, Burford N, Goldfarb V, Duke GJ, Shen H, Metzler W, Doyle M, Chen Z, Tarby C, Borzilleri R, Vaccaro W, Gottardis M, Lu S, Crews D, Kim K, Lombardo L, Roussell DL. Anal Biochem 392 59-69 (2009)
  12. Structure-activity relationship and liver microsome stability studies of pyrrole necroptosis inhibitors. Teng X, Keys H, Yuan J, Degterev A, Cuny GD. Bioorg Med Chem Lett 18 3219-3223 (2008)
  13. Monastrol analogs: a synthesis of pyrazolopyridine, benzopyranopyrazolopyridine, and oxygen-bridged azolopyrimidine derivatives and their biological screening. Svetlik J, Veizerová L, Mayer TU, Catarinella M. Bioorg Med Chem Lett 20 4073-4076 (2010)
  14. Docking studies on kinesin spindle protein inhibitors: an important cooperative 'minor binding pocket' which increases the binding affinity significantly. Jiang C, Chen Y, Wang X, You Q. J Mol Model 13 987-992 (2007)
  15. Design, synthesis and evaluation of tetrahydroisoquinolines as new kinesin spindle protein inhibitors. Jiang C, You Q, Liu F, Wu W, Guo Q, Chern J, Yang L, Chen M. Chem Pharm Bull (Tokyo) 57 567-571 (2009)
  16. Computational fragment-based drug design to explore the hydrophobic sub-pocket of the mitotic kinesin Eg5 allosteric binding site. Oguievetskaia K, Martin-Chanas L, Vorotyntsev A, Doppelt-Azeroual O, Brotel X, Adcock SA, de Brevern AG, Delfaud F, Moriaud F. J Comput Aided Mol Des 23 571-582 (2009)
  17. Synthetic studies of centromere-associated protein-E (CENP-E) inhibitors: 1.Exploration of fused bicyclic core scaffolds using electrostatic potential map. Hirayama T, Okaniwa M, Imada T, Ohashi A, Ohori M, Iwai K, Mori K, Kawamoto T, Yokota A, Tanaka T, Ishikawa T. Bioorg Med Chem 21 5488-5502 (2013)
  18. CPUYJ039, a newly synthesized benzimidazole-based compound, is proved to be a novel inducer of apoptosis in HCT116 cells with potent KSP inhibitory activity. Jiang C, Yang L, Wu WT, Guo QL, You QD. J Pharm Pharmacol 63 1462-1469 (2011)
  19. Discovery of Novel Allosteric Eg5 Inhibitors Through Structure-Based Virtual Screening. Zhang W, Zhai L, Lu W, Boohaker RJ, Padmalayam I, Li Y. Chem Biol Drug Des 88 178-187 (2016)
  20. Synthesis of pyrrolo[2,1-f][1,2,4]triazin-4(3H)-ones: Rearrangement of pyrrolo[1,2-d][1,3,4]oxadiazines and regioselective intramolecular cyclization of 1,2-biscarbamoyl-substituted 1H-pyrroles. Son K, Park SJ. Beilstein J Org Chem 12 1780-1787 (2016)
  21. Synthetic strategies for pyrrolo[2,1-f][1,2,4]triazine: the parent moiety of antiviral drug remdesivir. Rai GS, Maru JJ. Chem Heterocycl Compd (N Y) 56 1517-1522 (2020)
  22. Structure-based design of new KSP-Eg5 inhibitors assisted by a targeted multicomponent reaction. Carbajales C, Prado MÁ, Gutiérrez-de-Terán H, Cores A, Azuaje J, Novio S, Nuñez MJ, Fernández-García B, Sotelo E, García-Mera X, Sánchez-Lazo P, Freire-Garabal M, Coelho A. Chembiochem 15 1471-1480 (2014)


Quick links