Structure-activity relationships of a novel class of Src SH2 inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 16, 1999, Pages 2359-2364

  Buchanan, John L ^a   Vu, Chi B ^a   Merry, Taylor J ^a   Corpuz, Evelyn G ^a   Pradeepan, Selvaluxmi G ^a   Mani, Ukti N ^a   Yang, Michael ^a   Plake, Hilary R ^a   Varkhedkar, Vaibhav M ^a   Lynch, Berkley A ^a   MacNeil, Ian A ^a   Loiacono, Kara A ^a   Tiong, Choi Lai ^a   Holt, Dennis A ^a  

^a ARIAD PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HETEROCYCLIC COMPOUND; OXADIAZOLE DERIVATIVE; PROTEIN KINASE P60; PROTEIN TYROSINE KINASE INHIBITOR; TETRAPEPTIDE; THIAZOLE DERIVATIVE;

ARTICLE; BINDING AFFINITY; BREAST CANCER; DRUG STRUCTURE; DRUG SYNTHESIS; OSTEOPOROSIS; REACTION ANALYSIS; STRUCTURE ACTIVITY RELATION;

SRC HOMOLOGY DOMAINS; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLES;

EID: 0033575665     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(99)00389-3     Document Type: Article

References (22)

1. For a recent review on SH2 domains, see: Sawyer, T. K. Biopolymers 1998, 47, 243-261.
2. Thomas, S. M.; Brugge, J. S. Annu. Rev. Cell Dev. Biol. 1997, 13, 513-609.
3. Brown, M. T.; Cooper, J. A. Biochim. Biophys. Acta 1996, 1287, 121-149.
4. Hall, T. J.; Schaeublin, M.; Missbach, M. Biochem. Biophys. Res. Comm. 1994, 199, 1237-1244.
5. Boyce, B. F.; Yoneda, T.; Lowe, C.; Soriano, P.; Mundy, G. R. J. Clin. Invest. 1992, 90, 1622-1627.
6. Soriano, P.; Montgomery, C.; Geske, R.; Bradley, A. Cell 1991, 64, 693-702.
7. 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.
8. Buchanan, J. L.; Bohacek, R. S.; Luke, G. P.; Hatada, M.; Lu, X.; Dalgarno, D. C.; Narula, S. S.; Yuan, R.; Holt, D. A., Bioorg. Med. Chem. Lett., 1999, 9, 2353.
9. Waksman, G.; Shoelson, S. E.; Pant, N.; Cowburn, D.; Kuriyan, J. Cell 1993, 72, 779-790.
10. Tong, L.; Warren, T. C.; King, J.; Betageri, R.; Rose, J.; Jakes, S. J. Mol. Biol. 1996, 256, 601-610.
11. The protein numbering has been defined by Eck, M. J.; Shoelson, S. E.; Harrison, S. C. Nature 1993, 362, 87-91.
12. Aguilar, E.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 2473-2476 and references cited therein.
13. Bredenkamp, M. W.; Holzapfel, C. W.; van Zyl, W. J. Synth. Commun. 1990, 20, 2235-2249.
14. For representative experimental procedures, see: Buchanan, J. L.; Bohacek, R. S.; Vu, C. B.; Luke, G. P. "Heterocyclic Signal Transduction Inhibitors, Compositions Containing them & Uses Thereof." PCT US99/05970, March 18, 1999. All compounds were purified to homogeneity by reverse phase HPLC or crystallization and exhibited satisfactory analytical and spectroscopic properties.
15. Buchanan, J. L.; Mani, U. N.; Plake, H. R.; Holt, D. A. Tetrahedron Lett. 1999, 40, 3985-3988.
16. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-3818.
17. Anwer, M. K.; Spatola, A. F. Synthesis 1980, 929-932.
18. Borg, S.; Estenne-Bouhtou, G.; Luthman, K.; Csöregh, I.; Hesselink, W.; Hacksell, U. J. Org. Chem. 1995, 60, 3112-3120.
19. 50 by a factor of four.
20. 3 substituents in Table 1 continue to align the heterocycle ring away from the Tyr βD5 hydrophobic surface as shown in Figure 3 of ref. 8, or (b) the differences in the electronic character of the chosen heterocycles do not significantly affect the subsequent ligand binding affinities.
21. The nitriles chosen for pY+3 were based on a biased selection of commercially available nitriles that could potentially bind in the pY+3 pocket. In addition, several nitriles were chosen based on structural analysis based on the X-ray structure of 1b (R. S. Bohacek, unpublished results).
22. 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.