Discovery of novel 4-amino-6-arylaminopyrimidine-5-carbaldehyde oximes as dual inhibitors of EGFR and ErbB-2 protein tyrosine kinases.
We herein disclose a novel series of 4-aminopyrimidine-5-carbaldehyde oximes that are potent and selective inhibitors of both EGFR and ErbB-2 tyrosine kinases, with IC(50) values in the nanomolar range. Structure-activity relationship (SAR) studies elucidated a critical role for the 4-amino and C-6 arylamino moieties. The X-ray co-crystal structure of EGFR with 37 was determined and validated our design rationale.
Johnson & Johnson Pharmaceutical Research & Development, Medicinal Chemistry, 8 Clarke Drive, Cranbury, NJ 08512, USA. gxu4@prdus.jnj.com
Guozhang
G
Xu
Lily Lee
LL
Searle
Terry V
TV
Hughes
Amanda K
AK
Beck
Peter J
PJ
Connolly
Marta C
MC
Abad
Michael P
MP
Neeper
Geoffrey T
GT
Struble
Barry A
BA
Springer
Stuart L
SL
Emanuel
Robert H
RH
Gruninger
Niranjan
N
Pandey
Mary
M
Adams
Sandra
S
Moreno-Mazza
Angel R
AR
Fuentes-Pesquera
Steven A
SA
Middleton
Lee M
LM
Greenberger
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D066246:ErbB Receptors; D010091:Oximes; D011743:Pyrimidines; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human