Aromatic interactions with phenylalanine 691 and cysteine 828: A concept for FMS-like tyrosine kinase-3 inhibition. Application to the discovery of a new class of potential antileukemia agents

Journal of Medicinal Chemistry

Volumn 49, Issue 15, 2006, Pages 4451-4454

  Furet, Pascal ^a   Bold, Guido ^a   Meyer, Thomas ^a   Roesel, Johannes ^a   Guagnano, Vito ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

6,7 DIMETHYL 2 PHENYLQUINOXALINE; ADENOSINE TRIPHOSPHATE; CYSTEINE; D 64406; FMS LIKE TYROSINE KINASE 3 INHIBITOR; PHENYLALANINE; PROTEIN TYROSINE KINASE INHIBITOR; SEMAXANIB; UNCLASSIFIED DRUG;

ACUTE GRANULOCYTIC LEUKEMIA; ARTICLE; DRUG DESIGN; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME CONFORMATION; ENZYME INHIBITION; IC 50; MOLECULAR INTERACTION; PROTEIN DOMAIN; REACTION ANALYSIS; STRUCTURE ANALYSIS; VALIDATION PROCESS;

ACUTE DISEASE; ADENOSINE TRIPHOSPHATE; ANTINEOPLASTIC AGENTS; BINDING SITES; CELL LINE, TUMOR; CYSTEINE; FMS-LIKE TYROSINE KINASE 3; HUMANS; LEUKEMIA, MYELOID; MODELS, MOLECULAR; MUTATION; PHENYLALANINE; PROTEIN STRUCTURE, TERTIARY; THIAZOLES;

EID: 33746716196     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm060368s     Document Type: Article

References (29)

1. Sternberg, D. W.; Licht, J. D. Therapeutic intervention in leukemias that express the activated fms-like tyrosine kinase 3 (FLT3): opportunities and challenges. Curr. Opin. Hematol. 2005, 12, 7-13.
2. Advani, A. S. FLT3 and acute myelogenous leukemia: biology, clinical significance and therapeutic applications. Curr. Pharm. Des. 2005, 11, 3449-3457.
3. Heinrich, M. C. Targeting FLT3 kinase in acute myelogenous leukemia: progress, perils and prospects. Mini-Rev. Med. Chem. 2004, 4, 255-271.
4. Levis, M.; Small, D. FLT3: ITDoes matter in leukemia. Leukemia 2003, 17, 1738-1752.
5. Gilliland, D. G.; Griffin, J. D. The roles of FLT3 in hematopoiesis and leukemia. Blood 2002, 100, 1532-1542.
6. Stirewalt, D. L.; Radich, J. P. The role of FLT3 in haematopoietic malignancies. Nat. Rev. Cancer 2003, 3, 650-665.
7. Nakao, M.; Yokota, S.; Iwai, T.; Kaneko, H.; Horiike, S.; Kashima, K.; Sonoda, Y.; Fujimoto, T.; Misawa, S. Internal tandem duplication of the FLT3 gene found in acute myeloid leukemia. Leukemia 1996, 10, 1911-1918.
8. Levis, M.; Small, D. Novel FLT3 tyrosine kinase inhibitors. Expert Opin. Invest. Drugs 2003, 12, 1951-1962.
9. Weisberg, E.; Boulton, C.; Kelly, L. M.; Manley, P.; Fabbro, D.; Meyer, T.; Gilliland, D. G.; Griffin, J. D. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell 2002, 1, 433-443.
10. 11 In this structure, the ATP binding site is obstructed by residue Phe830 of the activation loop ("DFG out" conformation), which in principle precludes its use for docking the inhibitors of our study. However, we could derive a model of the ATP binding site corresponding to an active conformation from this structure by changing the conformation of the DGF motif to a "DFG in" conformation. Docking the inhibitors using this model gives the same results as with the homology model. Details of protein model construction and inhibitor docking are given in the Supporting Information.
11. Griffith, J.; Black, J.; Faerman, C.; Swenson, L.; Wynn, M.; Lu, F.; Lippke, J.; Saxena, K. The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Mol. Cell 2004, 13, 169-178.
12. Yee, K. W. H.; O'Farrell, A. M.; Smolich, B. D.; Cherrington, J. M.; McMahon, G.; Wait, C. L.; McGreevey, L. S.; Griffith, D. J.; Heinrich, M. C. SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase. Blood 2002, 100, 2941-2949.
13. Levis, M.; Tse, K.-F.; Smith, B. D.; Garrett, E.; Small, D. A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations. Blood 2001, 98, 885-887.
14. Tse, K. F.; Novelli, E.; Civin, C. I.; Bohmer, F. D.; Small, D. Inhibition of FLT3 mediated transformation by use of a tyrosine kinase inhibitor. Leukemia 2001, 15, 1001-1010.
15. Teller, S.; Kraemer, D.; Boehmer, S.-A.; Tse, K. F.; Small, D.; Mahboobi, S.; Wallrapp, C.; Beckers, T.; Kratz-Albers, K.; Schwaeble, J.; Serve, H.; Boehmer, F.-D. Bis(1H-2-indolyl)-1-methanones as inhibitors of the hematopoietic tyrosine kinase Flt3. Leukemia 2002, 16, 1528-1534.
16. Traxler, P.; Furet, P. Strategies towards the design of novel and selective protein tyrosine kinase inhibitors. Pharmacol. Ther. 1999, 82, 195-206.
17. The lactam ring in 1, the pyrazine ring in 2, and the bis-pyrrolyl methanone moiety in 3.
18. The three inhibitors accept a hydrogen bond from the backbone NH group of Cys694. 1 and 3 donate a hydrogen bond to the backbone carbonyl group of Glu692. 3 gives in addition a hydrogen bond to the backbone carbonyl group of Cys694.
19. The pyrrole ring in 1, the phenyl ring fused to the pyrazine ring in 2, and the phenol ring in 3.
20. For a detailed description of these two types of intermolecular interactions see ref 21 and references therein. By S-H/π interaction, it is meant an interaction between the thiol group of Cys828 and a phenyl ring of the inhibitor in which the side chain sulfur atom is positioned 3.5-4.0 Å below the plane of the phenyl ring with the thiol proton pointing towards its center. Such an interaction, also termed aromatic-thiol π hydrogen bond, has been calculated to provide 2.6 kcal/mol of stabilization energy (gas phase) in ref 22. Aromatic-aromatic edge to face interactions are more common and are very well reviewed in ref 21.
21. Meyer, E. A.; Castellano, R. K.; Diederich, F. Interactions with aromatic rings in chemical and biological recognition. Angew. Chem., Int. Ed. 2003, 42, 1210-1250.
22. Duan, G.; Smith, V. H., Jr.; Weaver, D. F. Characterization of aromatic-thiol π-type hydrogen bonding and phenylalanine-cysteine side chain interactions through ab initio calculations and protein database analyses. Mol. Phys. 2001, 99, 1689-1699.
23. Hanks, S. K.; Quinn, A.-M. Protein kinase catalytic domain sequence database: identification of conserved features of primary structure and classification of family members. Methods Enzymol. 1991, 200, 38-62.
24. Vieth, M.; Higgs, R. E.; Robertson, D. H.; Shapiro, M.; Gragg, E. A.; Hemmerle, H. Kinomics-structural biology and chemogenomics of kinase inhibitors and targets. Biochim. Biophys. Acta 2004, 1697, 243-257.
25. Cherry, M.; Williams, D. H. Recent kinase and kinase inhibitor X-ray structures: mechanisms of inhibition and selectivity insights. Curr. Med. Chem. 2004, 11, 663-673.
26. Manuscript in preparation.
27. For instance, 4 is expected to have a different interaction energy in the hydrophobic region II for CDK1 compared to FLT3 because CDK1 has a deletion in this region; the residue corresponding to Gly697 does not exist in CDK1.
28. 50 values of 0.040, 0.006, and 0.024 μM in the BaF3-ITD, BaF3-D835/Y, and MV4:11 assays, respectively.
29. As control, 4 was also tested on the wild-type BaF3 cell line. No significant inhibition of the proliferation of these cells, whose growth is independent of FLT3 signaling, was obtained at concentrations up to 3 μM.