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Inhibitors of human mitotic kinesin Eg5: characterization of the 4-phenyl-tetrahydroisoquinoline lead series.

Tarby CM, Kaltenbach RF, Huynh T, Pudzianowski A, Shen H, Ortega-Nanos M, Sheriff S, Newitt JA, McDonnell PA, Burford N, Fairchild CR, Vaccaro W, Chen Z, Borzilleri RM, Naglich J, Lombardo LJ, Gottardis M, Trainor GL, Roussell DL
Bioorg Med Chem Lett 16 2095-100 (2006)
Cited: 25 times
EuropePMC logo PMID: 16458511

Abstract

In a high-throughput screening effort, a series of tetrahydroisoquinolines was identified as modest inhibitors of human Eg5. A medicinal chemistry optimization effort led to the identification of R-4-(3-hydroxyphenyl)-N,N-7,8-tetramethyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (32a) as a potent inhibitor of human Eg5 (ATPase IC50 104 nM) with good anti-proliferative activity in A2780 cells (IC50 234 nM).

Articles - 2fme mentioned but not cited (3)

  1. Allosteric drug discrimination is coupled to mechanochemical changes in the kinesin-5 motor core. Kim ED, Buckley R, Learman S, Richard J, Parke C, Worthylake DK, Wojcik EJ, Walker RA, Kim S. J Biol Chem 285 18650-18661 (2010)
  2. Inhibition of hepatitis C virus NS5B polymerase by S-trityl-L-cysteine derivatives. Nichols DB, Fournet G, Gurukumar KR, Basu A, Lee JC, Sakamoto N, Kozielski F, Musmuca I, Joseph B, Ragno R, Kaushik-Basu N. Eur J Med Chem 49 191-199 (2012)
  3. Synthesis and characterization of tritylthioethanamine derivatives with potent KSP inhibitory activity. Rodriguez D, Ramesh C, Henson LH, Wilmeth L, Bryant BK, Kadavakollu S, Hirsch R, Montoya J, Howell PR, George JM, Alexander D, Johnson DL, Arterburn JB, Shuster CB. Bioorg Med Chem 19 5446-5453 (2011)


Reviews citing this publication (2)

  1. Advances in the discovery of kinesin spindle protein (Eg5) inhibitors as antitumor agents. El-Nassan HB. Eur J Med Chem 62 614-631 (2013)
  2. Actin- and microtubule-targeting bioprobes: their binding sites and inhibitory mechanisms. Usui T. Biosci Biotechnol Biochem 71 300-308 (2007)

Articles citing this publication (20)

  1. The discovery of tetrahydro-beta-carbolines as inhibitors of the kinesin Eg5. Barsanti PA, Wang W, Ni ZJ, Duhl D, Brammeier N, Martin E, Bussiere D, Walter AO. Bioorg Med Chem Lett 20 157-160 (2010)
  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. 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 3937-3942 (2006)
  6. Inhibitors of kinesin Eg5: antiproliferative activity of monastrol analogues against human glioblastoma cells. Müller C, Gross D, Sarli V, Gartner M, Giannis A, Bernhardt G, Buschauer A. Cancer Chemother Pharmacol 59 157-164 (2007)
  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. Structure-activity relationships and molecular docking of novel dihydropyrimidine-based mitotic Eg5 inhibitors. Prokopcová H, Dallinger D, Uray G, Kaan HY, Ulaganathan V, Kozielski F, Laggner C, Kappe CO. ChemMedChem 5 1760-1769 (2010)
  12. 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)
  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. Synthesis, physicochemical characterization, cytotoxicity, antimicrobial, anti-inflammatory and psychotropic activity of new N-[1,3-(benzo)thiazol-2-yl]-ω-[3,4-dihydroisoquinolin-2(1H)-yl]alkanamides. Zablotskaya A, Segal I, Geronikaki A, Eremkina T, Belyakov S, Petrova M, Shestakova I, Zvejniece L, Nikolajeva V. Eur J Med Chem 70 846-856 (2013)
  16. 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)
  17. Estrogen-dependent regulation of Eg5 in breast cancer cells. Planas-Silva MD, Filatova IS. Anticancer Drugs 18 773-779 (2007)
  18. Gold(I)-catalyzed domino reaction of aziridinyl alkynes. Zhang Z, Shi M. Chemistry 16 7725-7729 (2010)
  19. 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)
  20. 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)


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