Discovery of 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine (EP128265, MPI-0441138) as a potent inducer of apoptosis with high in vivo activity.
Using a live cell, high-throughput caspase-3 activator assay, we have identified a novel series of 4-anilinoquinazolines as inducers of apoptosis. In this report, we discuss the discovery of 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine, compound 2b (EP128265, MPI-0441138) as a highly active inducer of apoptosis (EC50 for caspase activation of 2 nM) and as a potent inhibitor of cell proliferation (GI50 of 2 nM) in T47D cells. Compound 2b inhibited tubulin polymerization, was effective in cells overexpressing ABC transporter Pgp-1, and was efficacious in the MX-1 human breast and PC-3 prostate cancer mouse models. In contrast to the SAR of 4-anilinoquinazolines as EGFR kinase inhibitors, the methyl group on the nitrogen linker was essential for the apoptosis-inducing activity of 4-anilinoquinazolines and substitution in the 6- and 7-positions of the quinazoline core structure decreased potency.
Sirisoma
Nilantha
N
EpiCept Corporation, 6650 Nancy Ridge Drive, San Diego, California 92121, USA.
Kasibhatla
Shailaja
S
Pervin
Azra
A
Zhang
Hong
H
Jiang
Songchun
S
Willardsen
J Adam
JA
Anderson
Mark B
MB
Baichwal
Vijay
V
Mather
Gary G
GG
Jessing
Kevin
K
Hussain
Raouf
R
Hoang
Khanh
K
Pleiman
Christopher M
CM
Tseng
Ben
B
Drewe
John
J
Cai
Sui Xiong
SX
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
C531197:2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine; D011799:Quinazolines; D020169:Caspases