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Optimization of inhibitors of the tyrosine kinase EphB4. 2. Cellular potency improvement and binding mode validation by X-ray crystallography.

Lafleur K, Dong J, Huang D, Caflisch A, Nevado C
J Med Chem 56 84-96 (2013)
Related entries: 4gk3, 4gk4

Cited: 16 times
EuropePMC logo PMID: 23253074

Abstract

Inhibition of the tyrosine kinase erythropoietin-producing human hepatocellular carcinoma receptor B4 (EphB4) is an effective strategy for the treatment of solid tumors. We have previously reported a low nanomolar ATP-competitive inhibitor of EphB4 discovered in silico by fragment-based high-throughput docking combined with explicit solvent molecular dynamics simulations. Here we present a second generation of EphB4 inhibitors that show high inhibitory potency in both enzymatic and cell-based assays while preserving the appealing selectivity profile exhibited by the parent compound. In addition, respectable levels of antiproliferative activity for these compounds have been obtained. Finally, the binding mode predicted by docking and molecular dynamics simulations is validated by solving the crystal structures of three members of this chemical class in complex with the EphA3 tyrosine kinase whose ATP-binding site is essentially identical to that of EphB4.

Articles - 4gk2 mentioned but not cited (3)

  1. KLIFS: a structural kinase-ligand interaction database. Kooistra AJ, Kanev GK, van Linden OP, Leurs R, de Esch IJ, de Graaf C. Nucleic Acids Res 44 D365-71 (2016)
  2. Structural Analysis of the Binding of Type I, I1/2, and II Inhibitors to Eph Tyrosine Kinases. Dong J, Zhao H, Zhou T, Spiliotopoulos D, Rajendran C, Li XD, Huang D, Caflisch A. ACS Med Chem Lett 6 79-83 (2015)
  3. Prediction of kinase-inhibitor binding affinity using energetic parameters. Usha S, Selvaraj S. Bioinformation 12 172-181 (2016)


Reviews citing this publication (3)

  1. EphB4: A promising target for upper aerodigestive malignancies. Salgia R, Kulkarni P, Gill PS. Biochim Biophys Acta Rev Cancer 1869 128-137 (2018)
  2. The critical role of the interplays of EphrinB2/EphB4 and VEGF in the induction of angiogenesis. Du E, Li X, He S, Li X, He S. Mol Biol Rep 47 4681-4690 (2020)
  3. New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs. Shan Y, Wang B, Zhang J. Med Res Rev 38 1674-1705 (2018)

Articles citing this publication (10)

  1. Letter Specificity and mechanism-of-action of the JAK2 tyrosine kinase inhibitors ruxolitinib and SAR302503 (TG101348). Zhou T, Georgeon S, Moser R, Moore DJ, Caflisch A, Hantschel O. Leukemia 28 404-407 (2014)
  2. Discovery of BRD4 bromodomain inhibitors by fragment-based high-throughput docking. Zhao H, Gartenmann L, Dong J, Spiliotopoulos D, Caflisch A. Bioorg Med Chem Lett 24 2493-2496 (2014)
  3. Structured water molecules in the binding site of bromodomains can be displaced by cosolvent. Huang D, Rossini E, Steiner S, Caflisch A. ChemMedChem 9 573-579 (2014)
  4. Interactions of quercetin with receptor tyrosine kinases associated with human lung carcinoma. Baby B, Antony P, Vijayan R. Nat Prod Res 32 2928-2931 (2018)
  5. Current kinase inhibitors cover a tiny fraction of fragment space. Zhao H, Caflisch A. Bioorg Med Chem Lett 25 2372-2376 (2015)
  6. In silico design and molecular basis for the selectivity of Olinone toward the first over the second bromodomain of BRD4. Rodríguez Y, Gerona-Navarro G, Osman R, Zhou MM. Proteins 88 414-430 (2020)
  7. Anilinoquinazoline inhibitors of the RET kinase domain-Elaboration of the 7-position. Jordan AM, Begum H, Fairweather E, Fritzl S, Goldberg K, Hopkins GV, Hamilton NM, Lyons AJ, March HN, Newton R, Small HF, Vishwanath S, Waddell ID, Waszkowycz B, Watson AJ, Ogilvie DJ. Bioorg Med Chem Lett 26 2724-2729 (2016)
  8. Converting a weaker ATP-binding site inhibitor into a potent hetero-bivalent ligand by tethering to a unique peptide sequence derived from the same kinase. Kedika SR, Udugamasooriya DG. Org Biomol Chem 16 6443-6449 (2018)
  9. Understanding the mechanism of action of pyrrolo[3,2-b]quinoxaline-derivatives as kinase inhibitors. Unzue A, Jessen-Trefzer C, Spiliotopoulos D, Gaudio E, Tarantelli C, Dong J, Zhao H, Pachmayr J, Zahler S, Bernasconi E, Sartori G, Cascione L, Bertoni F, Śledź P, Caflisch A, Nevado C. RSC Med Chem 11 665-675 (2020)
  10. Reducing the Flexibility of Type II Dehydroquinase for Inhibition: A Fragment-Based Approach and Molecular Dynamics Study. Peón A, Robles A, Blanco B, Convertino M, Thompson P, Hawkins AR, Caflisch A, González-Bello C. ChemMedChem 12 1512-1524 (2017)


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