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

• Published in: Journal of medicinal chemistry Vol. 51; no. 15; pp. 4771 - 4779
• Main Authors: Sirisoma, Nilantha, Kasibhatla, Shailaja, Pervin, Azra, Zhang, Hong, Jiang, Songchun, Willardsen, J. Adam, Anderson, Mark B, Baichwal, Vijay, Mather, Gary G, Jessing, Kevin, Hussain, Raouf, Hoang, Khanh, Pleiman, Christopher M, Tseng, Ben, Drewe, John, Cai, Sui Xiong
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.08.2008; Amer Chemical Soc
• Subjects: Animals; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Brain - metabolism; Caspases - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Enzyme Activation - drug effects; General aspects; Humans; Life Sciences & Biomedicine; Medical sciences; Mice; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - metabolism; Quinazolines - pharmacology; Science & Technology; Structure-Activity Relationship; TYROSINE KINASE INHIBITORS; CASPASE INHIBITORS; GROWTH-FACTOR RECEPTOR; 4-ANILINOQUINAZOLINE CLASS; GAMBOGIC ACID; SMALL-MOLECULE INHIBITORS; ANTICANCER AGENTS; THROUGHPUT SCREENING ASSAY; CHEMICAL GENETICS APPROACH; BCL-2 PROTEINS; Antineoplastic agent; High throughput screening; Human; Solid tumor; Quinazoline derivatives; Rodentia; Antitubulin; In vitro; In vivo; Vertebrata; Mammalia; Cell line; Structure activity relation; Mouse; Animal; Chlorine Organic compounds; Colon; Mammary gland; Chemical synthesis; Antimitotic; Tumor cell; Aromatic amine; Apoptosis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm8003653

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.