Structure-based design and solid-phase parallel synthesis of phosphorylated nonpeptides to explore hydrophobic binding at the Src SH2 domain

Journal of Combinatorial Chemistry

Volumn 2, Issue 4, 2000, Pages 305-313

  Metcalf III, Chester A ^a   Eyermann, Charles J ^a   Bohacek, Regine S ^a   Haraldson, Chad A ^a   Varkhedkar, Vaibhav M ^a   Lynch, Berkley A ^a   Bartlett, Catherine ^a   Violette, Shelia M ^a   Sawyer, Tomi K ^a  

^a ARIAD PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BENZAMIDE DERIVATIVE; PROTEIN KINASE P60;

ARTICLE; BINDING SITE; CHEMISTRY; DRUG DESIGN; PHOSPHORYLATION; SRC HOMOLOGY DOMAIN; STRUCTURE ACTIVITY RELATION; SYNTHESIS; X RAY CRYSTALLOGRAPHY;

BENZAMIDES; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; PHOSPHORYLATION; PROTO-ONCOGENE PROTEINS PP60(C-SRC); SRC HOMOLOGY DOMAINS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0034219948     PISSN: 15204766     EISSN: None     Source Type: Journal    
DOI: 10.1021/cc990074a     Document Type: Article

References (54)

1. (a) Chang, Y.-T.; Gray, N. S.; Rosania, G. R.; Sutherlin, D. P.; Kwon, S.; Norman, T. C.; Sarohia, R.; Leost, M.; Meijer, L.; Schultz, P. G. Chem. Biol. 1999, 6, 361-375.
2. (b) Rohrer, S. P.; Birzin, E. T.; Mosley, R. T.; Berk, S. C.; Hutchins, S. M.; Shen, D.-M.; Xiong, Y.; Hayes, E. C.; Parmar, R. M.; Foor, F.; Mitra, S. W.; Degrado, S. J.; Shu, M.; Klopp, J. M.; Cai, S.-J.; Blake, A.; Chan, W. W. S.; Pasternak, A.; Yang, L.; Patchett, A. A.; Smith, R. G.; Chapman, K. T.; Schaeffer, J. M. Science 1998, 282, 737-740.
3. (c) Brady, S. F.; Stauffer, K. J.; Lumma, W. C.; Smith, G. M.; Ramjit, H. G.; Lewis, S. D.; Lucas, B. J.; Gardell, S. J.; Lyle, E. A.; Appleby, S. D.; Cook, J. J.; Holahan, M. A.; Stranieri, M. T.; Lynch Jr., J. J.; Lin, J. H.; Chen, I.-W.; Vastag, K.; Naylor-Olsen, A. M.; Vacca, J. P. J. Med. Chem. 1998, 41, 401-406.
4. For recent reviews, see: (d) Fahad, O.-A.; Ostrem, J. A. Drug Discovery Today 1998, 3, 223-231.
5. (e) Hoekstra, W. J.; Poulter, B. L. Curr. Med. Chem. 1998, 5, 195-204.
6. (f) Fecik, R. A.; Frank, K. E.; Gentry, E. J.; Menon, S. R.; Mitscher, L. A.: Telikepalli, H. Med. Res. Rev. 1998, 18, 149-185.
7. (g) Dolle, R. E. Mol. Diversity 1997, 2, 223-236.
8. (h) Lam, K. S. Anti-Cancer Drug Des. 1997, 12, 145-167.
9. (i) Balkenhohl, F.; Bussche-Hünnefeld, C. von dem; Lansky, A.; Zechel, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2288-2337.
10. (j) Ellman, J. A. Acc. Chem. Res. 1996, 29, 132-143.
11. Such a strategy utilizes the philosophy of "resin capture," as introduced by Armstrong and Keating: Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 2574-2583. See also: Brown, S. D.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 6331-6332.
12. Such a strategy utilizes the philosophy of "resin capture," as introduced by Armstrong and Keating: Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 2574-2583. See also: Brown, S. D.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 6331-6332.
13. For examples of structure-based methods used in combinatorial chemistry, see: (a) Antel, J. Curr. Opin. Drug Discovery Dev. 1999, 2, 224-233.
14. (b) Szardenings, K. A.; Harris, D.; Lam, S.; Shi, L.; Tien, D.; Wang, Y.; Patel, D. V.; Navre, M.; Campbell, D. A. J. Med. Chem. 1998, 41, 2194-2200.
15. (c) Kick, E. K.; Roe, D. C.; Skillman, A. G.; Liu, G.; Ewing, T. J. A.; Sun, Y.; Kuntz, I. D.; Ellman, J. A. Chem. Biol. 1997, 4, 297-307.
16. (d) Combs, A. P.; Kapoor, T. M.; Feng, S.; Chen, J. K.; Daude-Snow, L. F.; Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 287-288.
17. Songyang, Z.; Shoelson, S. E.; Chaudhuri, M.; Gish, G.; Pawson, T.; Haser, W. G.; King, F.; Roberts, T.; Ratnofsky, S.; Lechleider, R. J.; Neel, B. G.; Birge, R. B.; Fajardo, J. E.; Chou, M. M.; Hanafusa, H.; Schaffhausen, B.; Cantley, L. C. Cell 1993, 72, 767-778.
18. Pawson, T. Nature 1995, 373, 573-580.
19. Cohen, G. B.; Ren, R.; Baltimore, D. Cell 1995, 80, 237-248.
20. Botfield, M. C.; Green, J. Ann. Rep. Med. Chem. 1995, 30, 227-237.
21. Brugge, J. S. Science 1993, 260, 918-919.
22. Saltiel, A. R.; Sawyer, T. K. Chem. Biol. 1996, 3, 887-893.
23. Waksman, G.; Kominos, D.; Robertson, S. R.; Pant, N.; Baltimore, D.; Birge, R. B.; Cowburn, D.; Hanafusa, H.; Mayer, B. J.; Overduin, M.; Resh, M. D.; Rios, C. B.; Silverman, L.; Kuriyan, J. Nature 1992, 358, 646-653.
24. Waksman, G.; Shoelson, S. E.; Pant, N.; Cowburn, D.; Kuriyan, J. Cell 1993, 72, 779-790.
25. Bibbins, K. B.; Boeuf, H.; Varmus, H. E. Mol. Cell. Biol. 1993, 13, 7278-7287.
26. For a recent review, see: (a) Sawyer, T. K. Biopolymers (Pept. Sci.) 1998, 47, 243-261.
27. Also, see: (b) Lee, R. T.; Lawrence, D. S. J. Med. Chem. 1999, 42, 784-787.
28. (c) Llinas-Brunet, M.; Beaulieu, P. L.; Cameron, D. R.; Ferland, J.-M.; Gauthier, J.; Ghiro, E.; Gillard, J.; Gorys, V.; Poirier, M.; Rancourt, J.; Wernic, D.; Betageri, R.; Cardozo, M.; Jakes, S.; Lukas, S.; Patel, U.; Proudfoot, J.; Moss, N. J. Med. Chem. 1999, 42, 722-729.
29. (d) Schoepfer, J.; Fretz, H.; Gay, B.; Furet, P.; Garcia-Echeverria, C.; End, N.; Caravatti, G. Bioorg. Med. Chem. Lett. 1999, 9, 221-226.
30. (e) Alligood, K. J.; Charifson, P. S.; Crosby, R.; Consler, T. G.; Feldman, P. L.; Gampe, R. T., Jr.; Gilmer, T. M.; Jordan, S. R.; Milstead, M. W.; Mohr, C.; Peel, M. R.; Rocque, W.; Rodriguez, M.; Rusnak, D. W.; Shewchuk, L. M.; Sternbach, D. D. Bioorg. Med. Chem. Lett. 1998, 8, 1189-1194.
31. (f) Charifson, P. S.; Shewchuk, L. M.; Rocque, W.; Hummel, C. W.; Jordan, S. R.; Mohr, C.; Pacofsky, G. L.; Peel, M. R.; Rodriguez, M.; Sternbach, D. D.; Consler, T. G. Biochemistry 1997, 36, 6283-6293.
32. (g) Plummer, M. S.; Lunney, E. A.; Para, K. S.; Shahripour, A.; Stankovic, C. J.; Humblet, C.; Fergus, J. H.; Marks, J. S.; Herrera, R.; Hubbell, S.; Saltiel, A.; Sawyer, T. K. Bioorg. Med. Chem. 1997, 5, 41-47.
33. (h) Plummer, M. S.; Lunney, E. A.; Para, K. S.; Vara Prasad, J. V. N.; Shahripour, A.; Singh, J.; Stankovic, C. J.; Humblet, C.; Fergus, J. H.; Marks, J. S.; Sawyer, T. K. Drug Des. Discovery 1996, 13, 75-81.
34. (i) Rodriguez, M.; Crosby, R.; Alligood, K. J.; Gilmer, T. M.; Berman, J. Lett. Pept. Sci. 1995, 2, 1-6.
35. (j) Gilmer, T. M.; Rodriguez, M.; Jordan, S.; Crosby, R.; Alligood, K. J.; Green, M.; Kimery, M.; Wagner, C.; Kinder, D.; Charifson, P.; Hassell, A. M.; Willard, D.; Luther, M.; Rusnak, D.; Sternbach, D. D.; Mehrotra, M.; Peel, M.; Shampine, L.; Davis, R.; Robbins, J.; Patel, I. R.; Kassel, D.; Burkhart, W.; Moyer, M.; Bradshaw, T.; Berman, J. J. Biol. Chem. 1994, 269, 31711-31719.
36. (a) Violette, S. M.; Shakespeare, W. C.; Bartlett, C.; Guan, W.; Smith, J. A.; Rickles, R. J.; Bohacek, R. S.; Holt, D. A.; Baron, R.; Sawyer, T. K. Chem. Biol. 2000, 7, 225-235.
37. (b) Luke, G. P. and Holt, D. A. Tetrahedron: Asymmetry 1999, 10, 4393-4403.
38. (c) Buchanan, J. L.; Bohacek, R. S.; Luke, G. P.; Hatada, M. H.; Lu, X.; Dalgarno, D. C.; Narula, S. S.; Yuan, R.; Holt, D. A. Bioorg. Med. Chem. Lett. 1999, 9, 2353-2358.
39. (d) Buchanan, J. L.; Vu, C. B.; Merry, T. J.; Corpuz, E. G.; Pradeepan, S. G.; Mani, U. N.; Yang, M.; Plake, H. R.; Varkhedkar, V. M.; Lynch, B. A.; MacNeil, I. A.; Loiacono, K. A.; Tiong, C. L.; and Holt, D. A. Bioorg. Med. Chem. Lett. 1999, 9, 2359-2364.
40. (e) Metcalf, C. A., III; Vu, C. B.; Sundaramoorthi, R., Jacobsen, V. A.; Laborde, E. A.; Green, J.; Green, Y.; Macek, K. J.; Merry, T. J.; Pradeepan, S. G.; Uesugi, M.; Varkhedkar, V. M.; Holt, D. A. Tetrahedron Lett. 1998, 39, 3435-3438.
41. Plummer, M. S.; Holland, D. R.; Shahripour, A.; Lunney, E. A.; Fergus, J. H.; Marks, J. S.; McConnell, P.; Mueller, W. T.; Sawyer, T. K. J. Med. Chem. 1997, 40, 3719-3725.
42. Lunney, E. A.; Para, K. S.; Rubin, J. R.; Humblet, C.; Fergus, J. H.; Marks, J. S.; Sawyer, T. K. J. Am. Chem. Soc. 1997, 119, 12471-12476.
43. A recent X-ray structure (2.5 Å) of compound 1a (higher affinity diastereomer) complexed with Lck SH2 (S162C) shows engagement of its cyclohexylmethyl group in the pY+3 domain of the protein (Bohacek, R. S.; Dalgarno, D. C.; Hatada, M.; Jacobsen, V. E.; Lynch, B. A.; Macek, K. J.; Metcalf, C. A., III; Narula, S. S.; Violette, S. M.; Sawyer, T. K.; Weigele, M., submitted for publication). Therefore, modifications made to this end of the molecule are expected to interact with the pY+3 pocket.
44. Lunney, E. A.; Para, K. S.; Plummer, M. S.; Prasad, J. V. N. V.; Saltiel, A. R.; Sawyer, T. K.; Shahripour, A.; Singh, J.; Stankovic, C. J. WO97/12903.
45. Although we utilized the racemic salicylic template for our study, the chiral nonracemic (S)-amine (stereochemistry of higher affinity diastereomer) can be readily generated in 88-94% ee (ref 14b).
46. Argonaut Technologies, San Carlos, CA.
47. Silverberg, L. J.; Dillon, J. L.; Vemishetti, P. Tetrahedron Lett. 1996, 37, 771-774.
48. Lynch, B. A.; Loiacono, K. A.; Tiong, C. L.; Adams, S. E.; MacNeil, I. A. Anal. Biochem. 1997, 247, 77-82.
49. FLO97, Graphics and Molecular Mechanics Software for Drug Design. Available from Colin McMartin at Thistlesoft, e-mail: cmcma@ix.netcom.com.
50. At the time we were designing molecules for this study, no high-resolution crystal structures of Src SH2 were available for docking studies. Therefore, the Lck SH2-peptide crystal structure was used not only because of the high quality (1.0 Å) of the structure but also because the binding site of Lck SH2 is almost identical to that of Src SH2 (for the X-ray structure, see: Tong, L.; Warren, T. C.; King, J.; Betageri, R.; Rose, J.; Jakes, S. J. Mol. Biol. 1996, 256, 601-610). We have had success using this model in the design of high-affinity inhibitors of Src SH2 and in the accurate prediction of their binding mode prior to determination by X-ray crystallography and NMR (see ref 14c and ref 17).
51. McMartin, C.; Bohacek, R. S. J. Comput.-Aided Mol. Des. 1997, 11, 333-344.
52. 50 value due to differences in assay protocols, but nonetheless they are in the same range.
53. Bohacek, R. S.; McMartin, C. J. Med. Chem. 1992, 35, 1671-84.
54. 2H was added at 0°C upon which the resin mixture was stirred to ambient temperature overnight (14 h) and then processed as described.