Knowledge-based design of 7-azaindoles as selective B-Raf inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 16, 2008, Pages 4610-4614

  Tang, Jun ^a   Hamajima, Toshihiro ^b   Nakano, Masato ^b   Sato, Hideyuki ^b   Dickerson, Scott H ^a   Lackey, Karen E ^a  

^a GLAXOSMITHKLINE   (United States)

^b Development and Medical Affairs Division   (Japan)

Author keywords

7 Azaindole; B Raf kinase; Knowledge based design

Indexed keywords

7 AZAINDOLE DERIVATIVE; B RAF KINASE; PHOSPHOTRANSFERASE INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; DRUG INHIBITION; DRUG POTENCY; DRUG SYNTHESIS; ENZYME ASSAY; IC 50;

CHEMISTRY, PHARMACEUTICAL; DRUG DESIGN; HUMANS; INDOLES; INHIBITORY CONCENTRATION 50; MODELS, BIOLOGICAL; MODELS, CHEMICAL; MOLECULAR STRUCTURE; PHOSPHOTRANSFERASES; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS B-RAF; STRUCTURE-ACTIVITY RELATIONSHIP; SUBSTRATE SPECIFICITY;

EID: 48649100604     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.07.019     Document Type: Article

References (22)

1. Hopkins A.L., and Groom C.R. Nat. Rev. 1 (2002) 727
2. Melnikova I., and Golden J. Nat. Rev. Drug Discov. 3 (2004) 993
3. Nie Z., Perretta C., Erickson P., Margosiak S., Almassy R., Lu J., Averill A., Yager K.M., and Chu S. Bioorg. Med. Chem. Lett. 17 (2007) 4191
4. Tao Z.-F., Wang L., Stewart K.D., Chen Z., Gu W., Bui M.-H., Merta P., Zhang H., Kovar P., Johnson E., Park C., Judge R., Rosenberg S., Sowin T., and Lin N.-H. J. Med. Chem. 50 (2007) 1514
5. Collins I., Caldwell J., Fonseca T., Donald A., Bavetsias V., Hunter L.-J.K., Garrett M.D., Rowlands M.G., Aherne G.W., Davies T.G., Berdini V., Woodhead S.J., Davis D., Seavers L.C.A., Wyatt P.G., Workman P., and McDonald E. Bioorg. Med. Chem. 14 (2006) 1255
6. McGregor M.J. J. Chem. Inf. Model 47 (2007) 2374
7. J. Med. Chem. 50 (2007) 409
8. Liu Y., and Gray N.S. Nat. Chem. Biol. 2 (2006) 358
9. Southall N.T., and Ajay. J. Med. Chem. 49 (2006) 2103
10. Schreck R., and Rapp U.R. Intl. J. Cancer 119 (2006) 2261
11. Li N., Batt D., and Warmuth M. Curr. Opin. Investig. Drugs 8 (2007) 452
12. King A.J., Patrick D.R., Batorsky R.S., Ho M.L., Do H.T., Zhang S.Y., Kumar R., Rusnak D.W., Takle A.K., Wilson D.M., Hugger E., Wang L., Karreth F., Lougheed J.C., Lee J., Chau D., Stout T.J., May E.W., Rominger C.M., Schaber M.D., Luo L., Lakdawala A.S., Adams J.L., Contractor R.G., Smalley K.S.M., Herlyn M., Morrissey M.M., Tuveson D.A., and Huang P.S. Cancer Res. 66 (2006) 11100
13. Takle A.K., Brown M.-J.B., Davies S., Dean D.K., Francis G., Gaiba A., Hird A.W., King F.D., Lovell P.J., Naylor A., Reith A.D., Steadman J.G., and Wilson D.M. Bioorg. Med. Chem. 16 (2006) 378
14. 50 value.{A figure is presented}
15. Tang, J.; Nakano, M.; Hamajima, T. PCT Int. Application, WO2007090141. Enzyme and cellular assay description can be found in this patent. Cellular assays: B-Raf mediated phosphorylation of MEK1 was measured in the cellular assay. Expression constructs for B-Raf and FLAG-tagged MEK1 were co-transfected in 3T3 cells and gene expression was induced using the GeneSwitch (TM) system for inducible mammalian expression (Invitrogen). Four hours following the induction of expression of B-Raf and MEK1, cells were exposed to the test compounds for 2 h. The cells were lysed, and then an immunoassay was performed using anti-phospho-MEK1/2 (Cell Signaling Technologies) to detect the percent inhibition of MEK1 phosphorylation.
16. Thibault C., L'Heureux A., Bhide R.S., and Ruel R. Organic Lett. 5 (2003) 5023
17. Adams, D. R.; Bentley, J. M.; Davidson, J.; Duncton, M. A. J.; Porter, R. H. P. PCT Int. Application, WO2000044753.
18. Yoshida, I.; Yoneda, N.; Ohashi, Y.; Suzuki, S.; Miyamoto, M.; Miyazaki, F.; Seshimo, H.; Kamata, J.; Takase, Y.; Shirato, M.; Shimokubo, D.; Sakuma, Y.; Yokohama, H. PCT Int. Application, WO2002088107.
19. +.
20. 50 = 6.7).
21. Model built from X-ray crystal structure PDB ID 1UWH with MacroModel, Schrödinger LLC.
22. This was numbered as Cys532 in some recent papers, for example:. Tsai J., Lee J.T., Wang W., Zhang J., Cho H., Mamo S., Bremer R., Gillette S., Kong J., Haass N.K., Sproesser K., Li L., Smalley K.S.M., Fong D., Zhu Y.-L., Marimuthu A., Nguyen H., Lam B., Liu J., Cheung I., Rice J., Suzuki Y., Luu C., Settachatgul C., Shellooe R., Cantwell J., Kim S.-H., Schlessinger J., Zhang K.Y.J., West B.L., Powell B., Habets G., Zhang C., Ibrahim P.N., Hirth P., Artis D.R., Herlyn M., and Bollag G. Proc. Natl. Acad. Sci. USA 105 (2008) 3041