title: 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.
abstract: 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.
authors.affiliation: EpiCept Corporation, 6650 Nancy Ridge Drive, San Diego, California 92121, USA.
authors.forename: Nilantha
authors.initials: N
authors.lastname: Sirisoma
authors.forename: Shailaja
authors.initials: S
authors.lastname: Kasibhatla
authors.forename: Azra
authors.initials: A
authors.lastname: Pervin
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Songchun
authors.initials: S
authors.lastname: Jiang
authors.forename: J Adam
authors.initials: JA
authors.lastname: Willardsen
authors.forename: Mark B
authors.initials: MB
authors.lastname: Anderson
authors.forename: Vijay
authors.initials: V
authors.lastname: Baichwal
authors.forename: Gary G
authors.initials: GG
authors.lastname: Mather
authors.forename: Kevin
authors.initials: K
authors.lastname: Jessing
authors.forename: Raouf
authors.initials: R
authors.lastname: Hussain
authors.forename: Khanh
authors.initials: K
authors.lastname: Hoang
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Pleiman
authors.forename: Ben
authors.initials: B
authors.lastname: Tseng
authors.forename: John
authors.initials: J
authors.lastname: Drewe
authors.forename: Sui Xiong
authors.initials: SX
authors.lastname: Cai
mesh_terms: 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
chemical_list: C531197:2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine; D011799:Quinazolines; D020169:Caspases