Hormones and Growth FactorsIrreversible inhibition of epidermal growth factor receptor tyrosine kinase with In Vivo activity by N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide (CL-387,785)
Section snippets
Chemicals
Preparation of CL-387,785 began with 5-nitroanthranilonitrile. Formamidination using N,N-dimethylformamide dimethyl acetal (98% yield) followed by reduction of the nitro group with palladium on carbon and cyclohexene in refluxing methanol furnished N′-(4-amino-2-cyanophenyl)-N,N-dimethylformamidine (95% yield). Acylation with the mixed anhydride of tetrolic acid and isobutyl chloroformate gave N-[3-cyano-4-[[(dimethylamino)methylene]amino]phenyl]-2-butynamide (89% yield). In the final step,
Results
Using the homology model of EGF-R as a starting point and the observations by us and others [22] that the 6- and 7-positions of the quinazoline ring can tolerate considerable bulk, we proposed that CL-387,785 bound to EGF-R at the ATP-binding region with an orientation and conformation similar to that shown in Fig. 1. This orientation placed the bromoaniline side chain of CL-387,785 in a hydrophobic pocket surrounded by Pro770, Met769, Gln767, Ala719, Val702, and Leu820. The N1 nitrogen of the
Discussion
These data show that CL-387,785 is a specific inhibitor of EGF-R. The molecule bound covalently to EGF-R. Such binding inhibited autophosphorylation of EGF-R and blocked proliferation of tumor cells both in vitro and in vivo. It is likely that CL-387,785 inhibits c-erbB-2, since the growth of cells that overexpress the receptor was inhibited and the drug inhibited autophosphorylation of c-erbB-2 in cells. Further studies are underway to determine whether CL-387,785 directly binds to c-erbB-2 or
Acknowledgements
We thank Ms. L. Benmassoud, Ms. S. Carter, Ms. K. Collins, Mr. M. Damiani, Dr. P. Lassota, Mr. R. Jeyasselan, Ms. E. Lenox, Ms. R. Montoya, Ms. G. McLaughlin, Mr. S. Jones, and Mr. R. Yannuzzi for their excellent technical assistance, the Biotechnology Core Group at Wyeth-Ayerst for providing recombinant enzyme, and Drs. F. Loganzo, P. Frost, and J. Upeslacis for their critical review of this work.
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Present address: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115.