The discovery of potent cRaf1 kinase inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 10, Issue 3, 2000, Pages 223-226

  Lackey, Karen ^a   Cory, Michael ^a   Davis, Ronda ^a   Frye, Stephen V ^a   Harris, Philip A ^a   Hunter, Robert N ^a   Jung, David K ^a   McDonald, O Bradley ^a   McNutt, Robert W ^a   Peel, Michael R ^a   Rutkowske, Randy D ^a   Veal, James M ^a   Wood, Edgar R ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; BENZYLIDINE 1H INDOL 2 ONE DERIVATIVE; CRAF1 KINASE INHIBITOR; INDOLE DERIVATIVE; MITOGEN ACTIVATED PROTEIN KINASE; PHENOL; PROTEIN KINASE INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; CHEMICAL MODIFICATION; DRUG POTENCY; DRUG STRUCTURE; ENZYME ASSAY; INHIBITION KINETICS; PARTIAL DRUG SYNTHESIS; STRUCTURE ACTIVITY RELATION;

ENZYME INHIBITORS; MAP KINASE SIGNALING SYSTEM; PROTO-ONCOGENE PROTEINS C-RAF; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 17144460676     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(99)00668-X     Document Type: Article

References (21)

1. Daum G., Eisenmann-Tappe I., Fries H.-W., Troppmair J., Rapp U.R. TIBS. 19:1994;474.
2. Avruch J., Xian-feng Z., Kyriakis J.M. TIBS. 19:1994;279.
3. Moelling K., Heimann B., Beimling P., Rapp U.R. Nature. 312:1984;558.
4. Kolch W., Heidecker G., Lloyd P., Rapp U.R. Nature. 349:1991;426.
5. Monia B.P., Johnston J.F., Geiger T., Muller M., Fabbro D. Nature Medicine. 2(6):1996;668.
6. Gajewski T.F., Thompson C.B. Cell. 87:1996;589.
7. Wang H., Rapp U.R., Reed J.C. Cell. 87:1996;629.
8. Wang H.-G., Takayama S., Rapp U.R., Reed J.C. Proc. Natl. Acad. Sci. USA. 93:1996;7063.
9. Shiraishi T., Domoto T., Imai N., Shimada Y., Watanabe K. Biochem. Biophys. Res. Commun. 147(1):1987;322.
10. Lackey, K.; McDonald, O. B.; Wood, E.R. In-house unpublished results.
11. A similar approach was undertaken by workers at Sugen in their identification of VEGFR TK inhibitor: Sun, L.; Tran, N.; Tang, F.; Harald, A.; Hirth, P.; McMahon, G.; Tang, C. J. Med. Chem. 1998, 41, 2588.
12. Lackey, K. E.; McNutt, R. W., Jr.; Jung, D. K.; Harris, P. A.; Hunter, R. N., III; Veal, J. M.; Dickerson, S.; Peel, M. R. PCT Int. Appl., 144 pp CODEN: PIXXD2. WO 9910325 A1 990304. AN 1999:166598 and references contained therein.
13. McDonald O.B., Chen W.J., Ellis B., Hoffman C., Overton L., Rink M., Smith A., Marshall C.J., Wood E.R. Analytical Biochem. 268:1999;318.
14. Kim S.-H., Schulze-Gahmen U., Brandsen J., de Azevedo W.F. Prog. Cell Cycle Res. 2:1996;137.
15. Mohammadi M., McMahon G., Sun L., Tang C., Hirth P., Yeh B.K., Hubbard S.R., Schlessinger J. Science. 276:1997;955.
16. a values were determined using a spectrophotometric method developed in our laboratory. Similar methods are discussed in Albert, A.; Serjeant, E. P. The determination of Ionization Constants, 2nd ed., Edinburgh, T.&A. Constable Ltd., 1971.
17. 13C NMR trends.
18. 2=0.92, F=206.81, n=20, P>0.01.
19. EMAPK: The EMAPK assay measures the EGF stimulated MAP kinase activation in a cellular assay format. Cells were serum starved for 24 h. cRaf1 inhibitors were pre-incubated with the cells for 60 min. The cells were stimulated with EGF (100 nM) for 5 min. The cells were lysed in SDS polyacrylamide gel sample buffer and the protein samples were resolved by SDS-PAGE. ERK activation was evaluated by Western Blotting using Anti-Phospho ERK (New England BioLabs).
20. EGF receptor autophosphorylation was evaluated in a manner similar to that cited in note 13 using Anti-PY20.
21. Results of a variety of cellular assay systems with a subset of these compounds: Wood, E. R.; Crosby, R. M.; Davenport, E. A.; Gilmer, T. M.; Hunter, B. N.; Keith, B. R.; Lee, A. V.; McDonald, O. B.; Mullin, R. J.; Rusnak, D. W.; Lackey, K. E. Am. Assoc. Cancer Res. 1999, 40, 724.