title: Achieving selectivity between highly homologous tyrosine kinases: a novel selective erbB2 inhibitor.
abstract: The discovery of small molecule kinase inhibitors for use as drugs is a promising approach for the treatment of cancer and other diseases, but the discovery of highly specific agents is challenging because over 850 kinases are expressed in mammalian cells. Systematic modification of the 4-anilino functionality of a selective quinazoline inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase can invert selectivity to favor inhibition of the highly homologous erbB2 tyrosine kinase. The selectivity pattern was demonstrated in assays of recombinant kinases and recapitulated in measures of kinase activity in intact cells. The most potent and selective erbB2 inhibitor of the analog series has anti-proliferative activity against an erbB2-overexpressing cell line that was lacking in the original EGFR-selective compound. Subtle changes to the molecular structure of ATP-competitive small molecule inhibitors of tyrosine kinases can yield dramatic changes in potency and selectivity. These results suggest that the discovery of highly selective small molecule inhibitors of very homologous kinases is achievable.
authors.affiliation: Pfizer Global Research and Development, Cancer Drug Discovery, Groton, CT 06340, USA.
authors.forename: Samit K
authors.initials: SK
authors.lastname: Bhattacharya
authors.forename: Eric D
authors.initials: ED
authors.lastname: Cox
authors.forename: John C
authors.initials: JC
authors.lastname: Kath
authors.forename: Alan M
authors.initials: AM
authors.lastname: Mathiowetz
authors.forename: Joel
authors.initials: J
authors.lastname: Morris
authors.forename: James D
authors.initials: JD
authors.lastname: Moyer
authors.forename: Leslie R
authors.initials: LR
authors.lastname: Pustilnik
authors.forename: Kris
authors.initials: K
authors.lastname: Rafidi
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Richter
authors.forename: Chunyan
authors.initials: C
authors.lastname: Su
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Wessel
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000814:Aniline Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D000255:Adenosine Triphosphate; D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins