Ras oncoprotein inhibitors: The discovery of potent, ras nucleotide exchange inhibitors and the structural determination of a drug-protein complex

Bioorganic and Medicinal Chemistry

Volumn 5, Issue 1, 1997, Pages 125-133

  Taveras, A G ^a   Remiszewski, S W ^a   Doll, R J ^a   Cesarz, D ^a   Huang, E C ^a   Kirschmeier, P ^a   Pramanik, B N ^a   Snow, M E ^a   Wang, Y S ^a   Del Rosario, J D ^a   Vibulbhan, B ^a   Bauer, B B ^a   Brown, J E ^a   Carr, D ^a   Catino, J ^a   Evans, C A ^a   Girijavallabhan, V ^a   Heimark, L ^a   James, L ^a   Liberles, S ^a   Nash, C ^a   Perkins, L ^a   Senior, M M ^a   Tsarbopoulos, A ^a   Ganguly, A K ^a   Aust, R ^b   Brown, E ^b   Delisle, D ^b   Fuhrman, S ^b   Hendrickson, T ^b   Kissinger, C ^b   Love, R ^b   Sisson, W ^b   Villafranca, E ^b   Webber, S E ^b   more..

^a MERCK RESEARCH LABORATORIES   (United States)

^b AGOURON PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; BENZENESULFONAMIDE DERIVATIVE; ONCOPROTEIN; RAS PROTEIN; SCH 54292; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; CONFERENCE PAPER; DRUG DESIGN; GENE ACTIVATION; MASS SPECTROMETRY; MOLECULAR MODEL; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; ONCOGENE RAS; PROTEIN BINDING; STRUCTURE ACTIVITY RELATION;

CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; MAGNETIC RESONANCE SPECTROSCOPY; PROTO-ONCOGENE PROTEINS P21(RAS); SPECTROMETRY, MASS, FAST ATOM BOMBARDMENT;

EID: 0031012426     PISSN: 09680896     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0968-0896(96)00202-7     Document Type: Conference Paper

References (31)

1. 1. Barbacid, M. Eur. J. Clin. Invest. 1990, 20, 225.
2. 2. (a) Downward, J. Science 1992, 358, 282.;
3. (b) Feig, L. A. Curr. Opin. Cell Biol. 1994, 6, 204;
4. (c) Cherniack, A. D.; Klarlund, J. K.; Czech, M. P. J. Biol. Chem. 1994, 269, 4717.
5. 3. For other approaches to ras nucleotide exchange inhibitors see: (a) Noonan, T.; Brown, N.; Dudycz, L.; Wright, G. J. Med. Chem. 1991, 34, 1302;
6. (b) Wolin, R.; Wang, D.; Kelly, J.; Afonso, A.; James, L.; Kirschmeier, P.; McPhail, A. T. Bioorg. and Med. Chem. Lett. 1996, 6, 195;
7. (c) Hayakawa, Y. Kenkyu Hokoku - Asahi Garasu Zaidan 1990, 25, 221.
8. 4. (a) Tong, L; DeVos, A. M.; Milburn, M. V.; Kim, S. H. J. Mol. Biol. 1991, 217, 503;
9. (b) Pai, E. F.; Krengel, U.; Petsko, G. A.; Goody, R. S.; Kabsch, W; Wittinghofer, A. EMBO J. 1990, 9, 2351;
10. (c) The x-ray crystallographic structure of ras-GDP used in this study was determined and refined at 2.1 Å resolution, and in a novel space group such that the Switch II loop does not have lattice contacts which could influence its conformation (R. Love et al., Agouron Pharm., personal communication);
11. (d) The Switch II loop of ras-GDP determined in 2(c) was found to be fully 'ordered' (electron density visible) in crystals that were soaked in a buffer containing a high lactose concentration (100 mM). The physical basis for this ordering is unclear; there is insufficient density to support bound lactose molecules in this region. However, the lack of any crystallographic sugars suggests that the observed conformation is among a lower energy family, rather than one artificially restrained by a tightly bound, complementary ligand.
12. 5. (a) Dauksas, V.; Paplaitis, V. Chem. Technol. 1972, 14, 121.
13. (b) Jones, R. L.; Metcalfe, T. P.; Sexton, W. A. Biochem. J. 1949, 45, 143.
14. 6. Rondestverdt, C. S. Jr.; Johnson, T. A. Synthesis 1977, 850.
15. 7. For a description of the in vitro nucleotide exchange assay, see: Hall, A.; Self, A. J. J. Biol. Chem. 1986, 261, 10963.
16. 8. Ganguly, A. K.; Pramanik, B. N.; Tsarbopoulos, A.; Covey, T. R.; Huang, E. C.; Fuhrman, S. A. J. Am. Chem. Soc. 1992, 114, 6559.
17. 9. Ganguly, A. K.; Pramanik, B. N.; Huang, E. C.; Tsarbopoulos, A.; Girijavallabhan, V. M.; Liberles, S. Tetrahedron 1993, 49, 7985.
18. 10. Initial findings have been discussed previously: Huang, E. C.; Liberles, S.; Heimark, L.; Pramanik, B. N.; Ganguly, A. K. 'Characterization of GDP/GTP Binding Sites of p21-Ras Protein by Chemical Modification and ESI LC/MS', Presented at the 42nd ASMS Conference on Mass Spectrometry and Allied Topics 1994 (Proceedings 308; Chicago, Il.; 29 May-3 June, 1994).
19. 11. For a more detailed description of this procedure and its use in this and other studies of scientific interest, see: Pramanik, B. N. et al. (in preparation).
20. 12. Endoproteinase Lys-C specifically cleaves peptides at lysine amino acids. Succinylated lysines are not recognized by this enzyme and are therefore not proteolyzed.
21. 13. Barbacid, M. Ann. Rev. Biochem. 1997, 56, 779.
22. 14. (a) Evans, C. A.; Wang, Y. S.; Snow, M. E.; Pramanik, B.; Doll, R. J.; Remiszewski, S.; Taveras, A. G.; 'NMR (and other) Studies of Nucleotide Exchange in Ras p-21', Presented at the 15th Blue Hen NMR Symposium; University of Deleware; Newark, Deleware; 5 June 1995;
23. (b) Wuthrich, K. NMR of Proteins and Nucleic Acids; John Wiley & Sons: New York, 1986.
24. 15. Tolerances of < 0.4 Å did not provide any conformation of SCH-54292 which satisfied all interatomic distances.
25. 16. Campbell-Burk, S. L.; Domaille, P. J.; Starovasnik, M. A.; Boucher, W.; Laue, E. D. J. Biomol. NMR 1992, 2, 639.
26. 17. Kraulis, P. J.; Domaille, P. J.; Campbell-Burk, S. L.; Aken, T. V.; Laue, E. D. Biochemistry 1994, 33, 3515.
27. 2 penalty term was added to the energy for violations of the three intermolecular NOEs. No penalty terms corresponding to the intramolecular NOEs of SCH-54292 were imposed.
28. 19. Li, B-Q.; Kaplan, D.; Kung, H-f.; Kamata, T. Science 1992, 256, 1456.
29. 20. Hattori, S; Clanton, D. J.; Satoh, T.; Nakamura, S.; Kaziro, Y.; Kawakita, M; Shih, T. Y. Mol. Cellular Biol. 1987, 7, 1999.
30. 21. Satoh, T.; Nakamura, S.; Kaziro, Y. Mol. Cellular Biol. 1987, 7, 4553.
31. 1H resonance for the C(1) gylcosyl proton at δ 5.00 exhibited a coupling constant of 7.5 Hz which is consistent with a trans-diaxial, β stereochemistry as shown for 9 and SCH-54292.