4ztq › Citations

Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening.

Kilchmann F, Marcaida MJ, Kotak S, Schick T, Boss SD, Awale M, Gönczy P, Reymond JL
J Med Chem 59 7188-211 (2016)
Related entries: 4zs0, 4ztr, 4zts

Cited: 24 times
EuropePMC logo PMID: 27391133

Abstract

Here we report the discovery of a selective inhibitor of Aurora A, a key regulator of cell division and potential anticancer target. We used the atom category extended ligand overlap score (xLOS), a 3D ligand-based virtual screening method recently developed in our group, to select 437 shape and pharmacophore analogs of reference kinase inhibitors. Biochemical screening uncovered two inhibitor series with scaffolds unprecedented among kinase inhibitors. One of them was successfully optimized by structure-based design to a potent Aurora A inhibitor (IC50 = 2 nM) with very high kinome selectivity for Aurora kinases. This inhibitor locks Aurora A in an inactive conformation and disrupts binding to its activator protein TPX2, which impairs Aurora A localization at the mitotic spindle and induces cell division defects. This phenotype can be rescued by inhibitor-resistant Aurora A mutants. The inhibitor furthermore does not induce Aurora B specific effects in cells.

Articles - 4ztq mentioned but not cited (2)

  1. Antitumor activity of TY-011 against gastric cancer by inhibiting Aurora A, Aurora B and VEGFR2 kinases. Liu W, Lu Y, Chai X, Liu X, Zhu T, Wu X, Fang Y, Liu X, Zhang X. J Exp Clin Cancer Res 35 183 (2016)
  2. ReMODE: a deep learning-based web server for target-specific drug design. Wang M, Wang J, Weng G, Kang Y, Pan P, Li D, Deng Y, Li H, Hsieh CY, Hou T. J Cheminform 14 84 (2022)


Reviews citing this publication (7)

  1. Targeting the Small GTPase Superfamily through Their Regulatory Proteins. Gray JL, von Delft F, Brennan PE. Angew Chem Int Ed Engl 59 6342-6366 (2020)
  2. Aurora A Kinase Is a Priority Pharmaceutical Target for the Treatment of Cancers. Damodaran AP, Vaufrey L, Gavard O, Prigent C. Trends Pharmacol Sci 38 687-700 (2017)
  3. The impact of in silico screening in the discovery of novel and safer drug candidates. Rognan D. Pharmacol Ther 175 47-66 (2017)
  4. Small molecules inhibiting Keap1-Nrf2 protein-protein interactions: a novel approach to activate Nrf2 function. Zhuang C, Wu Z, Xing C, Miao Z. Medchemcomm 8 286-294 (2017)
  5. Artificial intelligence and big data facilitated targeted drug discovery. Liu B, He H, Luo H, Zhang T, Jiang J. Stroke Vasc Neurol 4 206-213 (2019)
  6. The current issues and future perspective of artificial intelligence for developing new treatment strategy in non-small cell lung cancer: harmonization of molecular cancer biology and artificial intelligence. Tanaka I, Furukawa T, Morise M. Cancer Cell Int 21 454 (2021)
  7. Clinical value of Xenopus kinesin-like protein 2 as a prognostic marker in patients with digestive system cancers: a systematic review and meta-analysis. Wang G, Wang Q, Li Z, Liu C, He X. Onco Targets Ther 11 1229-1243 (2018)

Articles citing this publication (15)

  1. Editorial The Ecstasy and Agony of Assay Interference Compounds. Aldrich C, Bertozzi C, Georg GI, Kiessling L, Lindsley C, Liotta D, Merz KM, Schepartz A, Wang S. ACS Cent Sci 3 143-147 (2017)
  2. Identification of potent and selective small molecule inhibitors of the cation channel TRPM4. Ozhathil LC, Delalande C, Bianchi B, Nemeth G, Kappel S, Thomet U, Ross-Kaschitza D, Simonin C, Rubin M, Gertsch J, Lochner M, Peinelt C, Reymond JL, Abriel H. Br J Pharmacol 175 2504-2519 (2018)
  3. Dynamics of human protein kinase Aurora A linked to drug selectivity. Pitsawong W, Buosi V, Otten R, Agafonov RV, Zorba A, Kern N, Kutter S, Kern G, Pádua RA, Meniche X, Kern D. Elife 7 e36656 (2018)
  4. Editorial The Ecstasy and Agony of Assay Interference Compounds. Aldrich C, Bertozzi C, Georg GI, Kiessling L, Lindsley C, Liotta D, Merz KM, Schepartz A, Wang S. ACS Med Chem Lett 8 379-382 (2017)
  5. Identification of Novel Potential Inhibitors of Pteridine Reductase 1 in Trypanosoma brucei via Computational Structure-Based Approaches and in Vitro Inhibition Assays. Kimuda MP, Laming D, Hoppe HC, Tastan Bishop Ö. Molecules 24 E142 (2019)
  6. Antiparasitic Effects of Selected Isoflavones on Flatworms. Faixová D, Hrčková G, Mačák Kubašková T, Mudroňová D. Helminthologia 58 1-16 (2021)
  7. Identifying Lysophosphatidic Acid Acyltransferase β (LPAAT-β) as the Target of a Nanomolar Angiogenesis Inhibitor from a Phenotypic Screen Using the Polypharmacology Browser PPB2. Poirier M, Awale M, Roelli MA, Giuffredi GT, Ruddigkeit L, Evensen L, Stooss A, Calarco S, Lorens JB, Charles RP, Reymond JL. ChemMedChem 14 224-236 (2019)
  8. Further Exploration of the Benzimidazole Scaffold as TRPC5 Inhibitors: Identification of 1-Alkyl-2-(pyrrolidin-1-yl)-1H-benzo[d]imidazoles as Potent and Selective Inhibitors. Sharma S, L Pablo J, Tolentino KT, Gallegos W, Hinman J, Beninato M, Asche M, Greka A, Hopkins CR. ChemMedChem 17 e202200151 (2022)
  9. Synthesis of Novel Halogenated Heterocycles Based on o-Phenylenediamine and Their Interactions with the Catalytic Subunit of Protein Kinase CK2. Winiewska-Szajewska M, Maciejewska AM, Speina E, Poznański J, Paprocki D. Molecules 26 3163 (2021)
  10. Discovery of novel drug-like antitubercular hits targeting the MEP pathway enzyme DXPS by strategic application of ligand-based virtual screening. Zhu D, Johannsen S, Masini T, Simonin C, Haupenthal J, Illarionov B, Andreas A, Awale M, Gierse RM, van der Laan T, van der Vlag R, Nasti R, Poizat M, Buhler E, Reiling N, Müller R, Fischer M, Reymond JL, Hirsch AKH. Chem Sci 13 10686-10698 (2022)
  11. Eco-friendly methods of synthesis and preliminary biological evaluation of sulfonamide derivatives of cyclic arylguanidines. Zaręba P, Drabczyk AK, Wnorowski A, Pindelska E, Latacz G, Jaśkowska J. Ultrason Sonochem 90 106165 (2022)
  12. Noise reduction and mask removal neural network for X-ray single-particle imaging. Bellisario A, Maia FRNC, Ekeberg T. J Appl Crystallogr 55 122-132 (2022)
  13. Development and Biological Evaluation of the First Highly Potent and Specific Benzamide-Based Radiotracer [18F]BA3 for Imaging of Histone Deacetylases 1 and 2 in Brain. Clauß O, Schäker-Hübner L, Wenzel B, Toussaint M, Deuther-Conrad W, Gündel D, Teodoro R, Dukić-Stefanović S, Ludwig FA, Kopka K, Brust P, Hansen FK, Scheunemann M. Pharmaceuticals (Basel) 15 324 (2022)
  14. Docking and three-dimensional quantitative structure-activity relationship analyses of imidazole and thiazolidine derivatives as Aurora A kinase inhibitors. Im C. Arch Pharm Res 39 1635-1643 (2016)
  15. Protein dynamics: The future is bright and complicated! Nam K, Wolf-Watz M. Struct Dyn 10 014301 (2023)


Quick links