New dual inhibitors of EGFR and HER2 protein tyrosine kinases

Brian E Fink; Gregory D Vite; Harold Mastalerz; John F Kadow; Soong-Hoon Kim; Kenneth J Leavitt; Karen Du; Donald Crews; Toomas Mitt; Tai W Wong; John T Hunt; Dolatrai M Vyas; John S Tokarski

doi:10.1016/j.bmcl.2005.07.027

New dual inhibitors of EGFR and HER2 protein tyrosine kinases

Bioorg Med Chem Lett. 2005 Nov 1;15(21):4774-9. doi: 10.1016/j.bmcl.2005.07.027.

Authors

Brian E Fink¹, Gregory D Vite, Harold Mastalerz, John F Kadow, Soong-Hoon Kim, Kenneth J Leavitt, Karen Du, Donald Crews, Toomas Mitt, Tai W Wong, John T Hunt, Dolatrai M Vyas, John S Tokarski

Affiliation

¹ Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, NJ 08543-4000, USA. [email protected]

PMID: 16111887
DOI: 10.1016/j.bmcl.2005.07.027

Abstract

A novel series of dual EGFR and HER2 inhibitors based on the pyrrolo[2,1-f][1,2,4]triazine nucleus is described. A general route toward their synthesis, which enables functionalization at multiple sites, has been developed. Biological evaluation in enzymatic and cell-based assays has identified a series of C-6 carbamates with potent biochemical and cellular activities.

MeSH terms

Binding Sites
Carbamates / chemical synthesis
Carbamates / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
ErbB Receptors / antagonists & inhibitors*
Humans
Models, Molecular
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor, ErbB-2 / antagonists & inhibitors*
Structure-Activity Relationship
Triazines / chemical synthesis
Triazines / pharmacology

Substances

Carbamates
Triazines
ErbB Receptors
Receptor Protein-Tyrosine Kinases
Receptor, ErbB-2