Virtual Screening and Synthesis of New Chemical Scaffolds as VEGFR-2 Kinase Inhibitors

Abstract

Background:

VEGFR-2 tyrosine kinase inhibitors are currently receiving high interest in drug discovery process as anticancer agents. We have used virtual screening techniques in order to discover new scaffolds that can be used for developing new VEGFR-2 kinase inhibitors.

Method:

Similarity ensemble approach was used to reduce the chemical space of ZINC database to select a subset of compounds. A validated structure-based pharmacophore was developed and adopted to screen the selected subset. Initial hits mapped to the pharmacophore were filtered using docking and scoring. Selected compounds were synthesized and biologically tested.

Results:

Compound 9 showed very good cytotoxicity profile against the NCI 60 cancer cell lines, while compound 8 showed reasonable inhibition of VEGFR-2 tyrosine kinase.

Conclusion:

Stepwise virtual screening of databases such as ZINC may result in new scaffolds for developing VEGFR-2 kinase inhibitors.

Key words

SEA prediction - pharmacophore - docking - VEGFR-2

• References

• 1 Saijo N, Tamura T, Nishio K. Strategy for the development of novel anticancer drugs. Canc Chem and Pharm 2003; 52: 97-101
• 2 Siemann DW. Tumor Vasculature: a Target for Anticancer Therapies. John Wiley & Sons, Ltd; 2006: 1-8
• 3 Grunewald M, Avraham I, Dor Y et al. VEGF-Induced Adult Neovascularization: Recruitment, Retention, and Role of Accessory Cells. Cell 2006; 124: 175-189
• 4 Holmes DI, Zachary I. The vascular endothelial growth factor (VEGF) family: angiogenic factors in health and disease. Genome Biol 2005; 6: 209
• 5 Silva SR, Bowen KA, Rychahou PG et al. VEGFR-2 expression in carcinoid cancer cells and its role in tumor growth and metastasis. Intl J Canc 2011; 128: 1045-1056
• 6 Dev IK, Dornsife RE, Hopper TM et al. Antitumour efficacy of VEGFR2 tyrosine kinase inhibitor correlates with expression of VEGF and its receptor VEGFR2 in tumour models. Br J Cancer 2004; 91: 1391-1398
• 7 Goodman VL, Rock EP, Dagher R et al. Approval Summary: Sunitinib for the Treatment of Imatinib Refractory or Intolerant Gastrointestinal Stromal Tumors and Advanced Renal Cell Carcinoma. Clin Can Res 2007; 13: 1367-1373
• 8 Boyer SJ. Small molecule inhibitors of KDR (VEGFR-2) kinase: an overview of structure activity relationships. Curr Top Med Chem 2002; 2: 973-1000
• 9 Keiser MJ, Roth BL, Armbruster BN et al. Relating protein pharmacology by ligand chemistry. Nat Biotech 2007; 25: 197-206
• 10 Harmange J-C, Weiss MM, Germain J et al. Naphthamides as Novel and Potent Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors: Design, Synthesis, and Evaluation. J Med Chem 2008; 51: 1649-1667
• 11 Shoemaker RH. The NCI60 human tumour cell line anticancer drug screen. Nat Rev Cancer 2006; 6: 813-823
• 12 Accelry’s Discovery Studio 2.5.5 , . San Diego: Accelrys Software Inc.; 2010
• 13 Hecker EA, Duraiswami C, Andrea TA et al. Use of Catalyst Pharmacophore Models for Screening of Large Combinatorial Libraries. J Chem Info and Comp Scie 2002; 42: 11204-11211
• 14 Scott RB. Cancer chemotherapy – the first twenty-five years. Br Med J 1970; 4: 259-265
• 15 Krüger DM, Evers A. Comparison of Structure- and Ligand-Based Virtual Screening Protocols Considering Hit List Complementarity and Enrichment Factors. ChemMedChem 2010; 5: 148-158
• 16 Wolber G, Langer T. LigandScout: 3-d pharmacophores derived from protein-bound Ligands and their use as virtual screening filters. J Chem Info and Mod 2005; 45: 160-169
• 17 Wolber G, Langer T. LigandScout: Interactive automated pharmacophore model generation from ligand-target complexes. Abstracts Papers of the American Chemical Society 2005; 229: U611-U611
• 18 Liu Y, Gray NS. Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol 2006; 2: 358-364
• 19 Choquette D, Teffera Y, Polverino A et al. Discovery of novel 1,2,3,4-tetrahydroisoquinolines and 3,4-dihydroisoquinoline-1(2H)-ones as potent and selective inhibitors of KDR: Synthesis, SAR, and pharmacokinetic properties. Bioorg & Med Chem Lett 2008; 18: 4054-4058
• 20 Potashman MH, Bready J, Coxon A et al. Design, Synthesis, and Evaluation of Orally Active Benzimidazoles and Benzoxazoles as Vascular Endothelial Growth Factor-2 Receptor Tyrosine Kinase Inhibitors. J Med Chem 2007; 50: 4351-4373
• 21 Frey RR, Curtin ML, Albert DH et al. 7-Aminopyrazolo[1,5-a]pyrimidines as Potent Multitargeted Receptor Tyrosine Kinase Inhibitors. J Med Chem 2008; 51: 3777-3787
• 22 Huang N, Shoichet BK, Irwin JJ. Benchmarking Sets for Molecular Docking. J Med Chem 2006; 49: 6789-6801
• 23 Hawkins PCD, Skillman AG, Nicholls A. Comparison of Shape-Matching and Docking as Virtual Screening Tools. J Med Chem 2006; 50: 74-82
• 24 Triballeau N, Acher F, Brabet I et al. Virtual Screening Workflow Development Guided by the “Receiver Operating Characteristic” Curve Approach. Application to High-Throughput Docking on Metabotropic Glutamate Receptor Subtype 4. J Med Chem 2005; 48: 2534-2547
• 25 Kakuta H, Zheng X, Oda H et al. Cyclooxygenase-1-selective inhibitors are attractive candidates for analgesics that do not cause gastric damage. design and in vitro/in vivo evaluation of a benzamide-type cyclooxygenase-1 selective inhibitor. J Med Chem 2008; 51: 2400-2411
• 26 Rode HB, Sprang T, Besch A et al. Pseudosaccharin amine derivatives: synthesis and elastase inhibitory activity. Pharmazie 2005; 60: 723-731
• 27 Romagnoli R, Baraldi PG, Remusat V et al. Synthesis and biological evaluation of 2-amino-3-(3′, 4′, 5′-trimethoxy-phenylsulfonyl)-5-aryl thiophenes as a new class of antitubulin agents. Med Chem 2007; 3: 507-512
• 28 Dumas J, Smith RA, Lowinger TB. Recent developments in the discovery of protein kinase inhibitors from the urea class. Curr Opin Drug Discov Devel 2004; 7: 600-616
• 29 Hu W-P, Chen Y-K, Yu H-S et al. Synthesis, and biological evaluation of 2-(4-aminophenyl)benzothiazole derivatives as photosensitizing agents. Bioorg and Med Chem 2010; 18: 6197-6207
• 30 Clark CR, Sansom RT, Lin C-M et al. Anticonvulsant Activity of Some 4-Aminobenzanilides. J Med Chem 1985; 28: 1259-1262
• 31 Bulman Page PC, Bethell D, Stocks PA et al. Sulfur Oxidation Mediated by Imine Derivatives. Synlett 1997; 12 (1355) 1358
• 32 Linn JA, Timothy L, Stevens KL et al. Lawrence Pyrimidine compounds useful as kinase inhibitors. Patent WO/2008/024634 2008
• 33 Naegeli C, Tyabji A, Conrad L. Über den Umsatz aromatischer Isocyansäure-ester mit aromatischen Aminen. Helvetica Chimica Acta 1938; 21: 1127-1143