Structure-based design and synthesis of a novel class of Src SH2 inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 16, 1999, Pages 2353-2358

  Buchanan, John L ^a   Bohacek, Regine S ^a   Luke, George P ^a   Hatada, Marcos ^a   Lu, Xiaode ^a   Dalgarno, David C ^a   Narula, Surinder S ^a   Yuan, Ruth ^a   Holt, Dennis A ^a  

^a ARIAD PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

PROTEIN KINASE P60; PROTEIN TYROSINE KINASE; PROTEIN TYROSINE KINASE INHIBITOR; THIAZOLE DERIVATIVE;

ARTICLE; DRUG SYNTHESIS; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PROTEIN DOMAIN; REACTION ANALYSIS; STEREOISOMERISM; STRUCTURE ACTIVITY RELATION; X RAY ANALYSIS;

CRYSTALLOGRAPHY, X-RAY; MAGNETIC RESONANCE SPECTROSCOPY; MOLECULAR STRUCTURE; SRC HOMOLOGY DOMAINS; THIAZOLES;

EID: 0033575680     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(99)00388-1     Document Type: Article

References (38)

1. For a recent review on SH2 domains, see: Sawyer, T. K. Biopolymers 1998, 47, 243-261.
2. For a review on Src kinase function, see: Thomas, S. M.; Brugge, J. S. Annu. Rev. Cell Dev. Biol. 1997, 13, 513-609.
3. Hall, T. J.; Schaeublin, M.; Missbach, M. Biochem. Biophys. Res. Comm. 1994, 199, 1237-1244.
4. Boyce, B. F.; Yoneda, T.; Lowe, C.; Soriano, P.; Mundy, G. R. J. Clin. Invest. 1992, 90, 1622-1627.
5. Soriano, P.; Montgomery, C.; Geske, R.; Bradley, A. Cell 1991, 64, 693-702.
6. Luttrell, D. K.; Lee, A.; Lansing, T. J.; Crosby, R. M.; Jung, K. D.; Willard, D.; Luther, M.; Rodriguez, M.; Berman, J.; Gilmer, T. M. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 83-87.
7. 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.
8. Stankovic, C. J. Src-Sh2 domain: Structure, specificity, and drug design. Presented at the 3rd Annual IBC Conference on New Advances in Peptidomimetics and Small Molecule Design, Washington, DC, March 1996.
9. 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 Design and Discovery 1996, 13, 75-81.
10. 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.
11. Shahripour, A.; Para, K. S.; Plummer, M. S.; Lunney, E. A.; Holland, D. R.; Rubin, J. R.; Humblet, C.; Fergus, J. H.; Marks, J. S.; Saltiel, A. R.; Sawyer, T. K. Bioorg. Med. Chem. Lett. 1997, 7, 1107-1112.
12. Stankovic, C. J.; Plummer, M. S.; Sawyer, T. K. Adv. Amino Acid Mimetics Peptidomimetics 1997, 1, 127-163.
13. Gilmer, T.; Rodriguez, M.; Jordan, S.; Crosby, R.; Alligood, K.; 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.
14. Rodriguez, M.; Crosby, R.; Alligood, K.; Gilmer, T.; Berman, J. Lett. Pept. Sci. 1995, 2, 1-6.
15. Charifson, P. S.; Shewchuk, L. M.; Rocque, W. Hummel, C. W.; Jordan, S. R.; Mohr, C.; Pacofsky, G. J.; Peel, M. R.; Rodriquez, M.; Sternbach, D. D.; Consler, T. G. Biochemistry 1997, 36, 6283-6293.
16. Pacofsky, G. J.; Lackey, K.; Alligood, K. J.; Berman, J.; Charifson, P. S.; Crosby, R. M.; Dorsey, G. F., Jr.; Feldman, P. L.; Gilmer, T. M.; Hummel, C. W.; Jordan, S. R.; Mohr, C.; Shewchuk, L. M.; Sternbach, D. D.; Rodriquez, M. J. Med. Chem. 1998, 41, 1894-1908.
17. Llinàs-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.
18. Waksman, G.; Shoelson, S. E.; Pant, N.; Cowburn, D.; Kuriyan, J. Cell 1993, 72, 779-790.
19. Tong, L.; Warren, T. C.; King, J.; Betageri, R.; Rose, J.; Jakes, S. J. Mol. Biol. 1996, 256, 601-610.
20. The protein numbering has been defined by Eck, M. J.; Shoelson, S. E.; Harrison, S. C. Nature 1993, 362, 87-91.
21. The SH2 binding sites for Lck and Src are nearly identical with only conservative modifications in a few residues. A model of the Src SH2 binding site has been developed using both Src and Lck structures. This model displays the Lee and Richards (ref. 22) accessible surfaces to highlight the areas of hydrophobic and hydrogen bonding interactions as in Figures 1-3. Ligands were examined using the QXP (ref. 23) docking program module of the FLO97 molecular modeling program.
22. Bohacek, R. S.; McMartin, C. J. Med. Chem. 1992, 35, 1671-1684.
23. McMartin, C.; Bohacek, R. S. J. Comput.-Aided Mol. Des. 1997, 11, 333-344.
24. A bridging strategy, using configurationally flexible linkers, was employed by the Glaxo group and resulted in 190- to 860-fold loss in binding affinity in the pYEEIE peptide series (see ref. 13).
25. Cyclohexyl has been demonstrated to be an effective pY+3 Ile side chain replacement (see ref. 10).
26. Nugent, W. A.; McKinney, R. J. J. Org. Chem. 1985, 50, 5370-5372 and references cited therein.
27. All compounds were purified to homogeneity and exhibited satisfactory analytical and spectroscopic properties.
28. Hajos, Z. G.; Wachter, M. P.; Werblood, H. M.; Adams, R. E. J. Org. Chem. 1984, 49, 2600-2608.
29. Katritzky, A. R.; Chen, J.; Yang, Z. J. Org. Chem. 1995, 60, 5638-5642 and references cited therein.
30. Aguilar, E.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 2473-2476 and references cited therein.
31. Bredenkamp, M. W.; Holzapfel, C. W.; van Zyl, W. J. Synth. Commun. 1990, 20, 2235-2249.
32. 50 by a factor of four.
33. b was cocrystallized with wild-type Lck SH2, which was used as a Src SH2 surrogate due to greater success with ligand cocrystallization. The structure was determined by molecular replacement methods and refined using X-PLOR (Brünger, A. X-PL-OR, Version 3.1. (Yale Univ. Press, New Haven, CT, 1992)). This Lck SH2 crystal structure correlated closely with the Src SH2 NMR structure (ref. 34) as well as that predicted from molecular modeling (ref. 21). In addition, the binding affinity of 3b in both Lck SH2 and Yes SH2 was equivalent to that reported here for Src SH2.
34. 15N-Src:ligand complex (Muhandiram, D. R.; Kay, L. E. J. Magn. Reson., Ser B 1994, 103, 203-216). Ligand protein and ligand:ligand NOE's were obtained using isotope filtered NMR methods (Ikura, M.; Bax, A. J. Am. Chem. Soc. 1992, 114, 2433-2440). A family of NMR structures was calculated based on 29 Src:ligand and 11 intraligand NOE's. The NMR structurecorrelated closely with the Lck X-ray structure as expected due to the similarities in Src and Lck SH2 (ref. 21, 33).
35. 15N-Src:ligandcomplex (Muhandiram, D. R.; Kay, L. E. J. Magn. Reson., Ser B 1994, 103, 203-216). Ligand protein and ligand:ligandNOE's were obtained using isotope filtered NMR methods (Ikura, M.; Bax, A. J. Am. Chem. Soc. 1992, 114, 2433-2440). A family of NMR structures was calculated based on 29 Src:ligand and 11 intraligand NOE's. The NMR structure correlated closely with the Lck X-ray structure as expected due to the similarities in Src and Lck SH2 (ref. 21, 33).
36. By definition, the Lee and Richards accessible surface depiction suggests that the optimal interaction would be gained with the thiazole ring situated directly on the yellow TyrβD5 hydrophobic surface.
37. Subsequent to these efforts, Parke-Davis reported a phenyl template designed to displace structural water with an amide group: 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.
38. 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.; Holt, D. A. Bioorg. Med. Chem. Lett. 1999, 9, 2359.