2. Academic Validation
  3. 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

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

  • J Med Chem. 2008 Aug 14;51(15):4771-9. doi: 10.1021/jm8003653.
Nilantha Sirisoma 1,  Shailaja Kasibhatla,  Azra Pervin,  Hong Zhang,  Songchun Jiang,  J Adam Willardsen,  Mark B Anderson,  Vijay Baichwal,  Gary G Mather,  Kevin Jessing,  Raouf Hussain,  Khanh Hoang,  Christopher M Pleiman,  Ben Tseng,  John Drewe,  Sui Xiong Cai
Affiliations

Affiliation

  • 1 EpiCept Corporation, 6650 Nancy Ridge Drive, San Diego, California 92121, USA.
PMID: 18651728 DOI: 10.1021/jm8003653
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.

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