Fwd: 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.

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From: HubMed - breast cancer <rssfwd@rssfwd.com>
Date: Fri, Jul 25, 2008 at 11:44 PM
Subject: 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.
To: mesothelioma77@gmail.com


[1]J Med Chem. 2008 Jul 24;
Sirisoma N, Kasibhatla S, Pervin A, Zhang H, Jiang S, Willardsen JA, Anderson MB, Baichwal V, Mather GG, Jessing K, Hussain R, Hoang K, Pleiman CM, Tseng B, Drewe J, Cai SX

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 (EC 50 for caspase activation of 2 nM) and as a potent inhibitor of cell proliferation (GI 50 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.



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Source: http://www.hubmed.org/display.cgi?uids=18651728
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