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.

Discovery of Biarylaminoquinazolines as Novel Tubulin Polymerization Inhibitors

“…10 Because this chemotype is quite unexplored as a class of tubulin inhibitors, we initiated a molecular modeling study with the goal of rationalizing the pivotal pharmacophore features required to achieve dual inhibition of tubulin polymerization and TKs. Some attempts to draw a common SAR were previously published, 10,11 but these were aimed mainly at determining differences between the requirements of the two targets.…”

Quinazoline–benzimidazole hybrid as dual optical sensor for cyanide and Pb2+ ions and Aurora kinase inhibitor

“…Many research groups have proved that the overexpression of Aurora-A induces several cancerassociated phenotypes, including enhanced cell proliferation and colony formation, and inhibition of apoptosis [39][40][41]. Some quinazoline derivatives interact with tubulin [42] and interfere with its polymerization, others act by modulating Aurora kinase activity [43][44] or have an effect in critical phases in the cell cycle [45] or act as apoptosis inducers [46][47]. Similarly compound 2 was also docked with active site of Aurora kinase inhibitor (pdb ID 2WTV (Figure 8b).…”

Exploration of Chemical Space Based on 4-Anilinoquinazoline

“…Nowadays many novel agents to activate and promote apoptosis in cancer cells via targeting regulators of apoptosis are being explored [98]. Some studies have reported structure activity relationship (SAR) on 4-anilinoquinazolines as potent apoptosis inducers and identified anticancer development candidate 66, which displayed in vivo anticancer activity and high BBB penetration [99]. To optimize this class of anticancer agents, the 2-Cl group in 66, a potential liability due to its chemical reactivity, is replaced by other functional groups.…”