4-Amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones as potent ErbB-2/EGFR dual kinase inhibitors.
Members of a novel class of 4-amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones were identified as potent dual ErbB-2/EGFR kinase inhibitors using concept-guided design approach. These compounds inhibited the growth of ErbB-2 over-expressing human tumor cell lines (BT474, N87, and SK-BR-3) in vitro. Compound 15 emerged as a key lead and showed significant ability to inhibit growth factor-induced receptor phosphorylation in SK-BR-3 cells (IC(50)=54 nM) and cellular proliferation in vitro (IC(50)=14, 58, and 58 nM for BT474, N87, and SK-BR-3 respectively). The X-ray co-crystal structure of EGFR with a close analog (17) was determined and validated our design rationale.
Xu
Guozhang
G
Johnson & Johnson Pharmaceutical Research and Development, Medicinal Chemistry, 8 Clarke Drive, Cranbury, NJ 08512, USA. gxu4@prdus.jnj.com
Abad
Marta C
MC
Connolly
Peter J
PJ
Neeper
Michael P
MP
Struble
Geoffrey T
GT
Springer
Barry A
BA
Emanuel
Stuart L
SL
Pandey
Niranjan
N
Gruninger
Robert H
RH
Adams
Mary
M
Moreno-Mazza
Sandra
S
Fuentes-Pesquera
Angel R
AR
Middleton
Steven A
SA
D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D010091:Oximes / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D066246:ErbB Receptors; D006835:Hydrazones; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D018719:Erb-b2 Receptor Tyrosine Kinases