The discovery of highly selective erbB2 (Her2) inhibitors for the treatment of cancer.
The synthesis and biological evaluation of potent and selective inhibitors of the erbB2 kinase is presented. Based on the 4-anilinoquinazoline chemotype, the syntheses of several new series of erbB2 inhibitors are described with quinazoline and pyrido[4,3-d]pyrimidine cores. The vast majority of these compounds are found to be >100x selective over the closely related EGFR kinase. Two lead compounds are further shown to have low clearance and moderate bioavailability in rat.
Lippa
Blaise
B
Pfizer, Inc., PGRD Groton, MS-8220-2203 Eastern Point Road, Groton, CT 06340, USA. blaise.lippa@pfizer.com
Kauffman
Goss S
GS
Arcari
Joel
J
Kwan
Tricia
T
Chen
Jinshan
J
Hungerford
William
W
Bhattacharya
Samit
S
Zhao
Xumiao
X
Williams
Courtney
C
Xiao
Jun
J
Pustilnik
Leslie
L
Su
Chunyan
C
Moyer
James D
JD
Ma
Ling
L
Campbell
Mary
M
Steyn
Stefanus
S
D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D045744:Cell Line, Tumor; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases