Discovery of N-(4-Methoxyphenyl)-N,2-dimethylquinazolin-4-amine, a Potent Apoptosis Inducer and Efficacious Anticancer Agent with High Blood Brain Barrier Penetration

1区 · 医学

Article

作者: Zhang, Hong ; Drewe, John ; Pleiman, Christopher M. ; Cai, Sui Xiong ; Mather, Gary ; Willardsen, J. Adam ; Anderson, Mark B. ; Pervin, Azra ; Kasibhatla, Shailaja ; Jiang, Songchun ; Tseng, Ben ; Sirisoma, Nilantha

As a continuation of our structure-activity relationship (SAR) studies on 4-anilinoquinazolines as potent apoptosis inducers and to identify anticancer development candidates, we explored the replacement of the 2-Cl group in our lead compound 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine (6b, EP128265, MPI-0441138) by other functional groups. This SAR study and lead optimization resulted in the identification of N-(4-methoxyphenyl)-N,2-dimethylquinazolin-4-amine (6h, EP128495, MPC-6827) as an anticancer clinical candidate. Compound 6h was found to be a potent apoptosis inducer with EC(50) of 2 nM in our cell-based apoptosis induction assay. It also has excellent blood brain barrier penetration, and is highly efficacious in human MX-1 breast and other mouse xenograft cancer models.

2008-08-01·Journal of Medicinal Chemistry1区 · 医学

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

1区 · 医学

Article

作者: Cai, Sui Xiong ; Mather, Gary G. ; Hussain, Raouf ; Tseng, Ben ; Jiang, Songchun ; Zhang, Hong ; Pervin, Azra ; Pleiman, Christopher M. ; Hoang, Khanh ; Drewe, John ; Jessing, Kevin ; Baichwal, Vijay ; Anderson, Mark B. ; Willardsen, J. Adam ; Kasibhatla, Shailaja ; Sirisoma, Nilantha

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.

2007-06-15·Cancer Research1区 · 医学

MPC-6827: A Small-Molecule Inhibitor of Microtubule Formation That Is Not a Substrate for Multidrug Resistance Pumps

1区 · 医学

Article

作者: Carlson, Robert O. ; Roth, Bruce ; Kasibhatla, Shailaja ; Skvortsov, Sergej ; Skvortsova, Ira ; Cai, Sui Xiong ; Pleiman, Christopher M. ; Drewe, John ; Baichwal, Vijay ; Tseng, Ben ; English, Nicole M. ; Sirisoma, Nilantha ; Pervin, Azra ; Lukas, Peter

AbstractA novel series of 4-arylaminoquinazolines were identified from a cell-based screening assay as potent apoptosis inducers. Through structure-activity relationship studies, MPC-6827 and its close structural analogue, MPI-0441138, were discovered as proapoptotic molecules and mitotic inhibitors with potencies at low nanomolar concentrations in multiple tumor cell lines. Photoaffinity and radiolabeled analogues of MPC-6827 were found to bind a 55-kDa protein, and this binding was competed by MPC-6827, paclitaxel, and colchicine, but not vinblastine. MPC-6827 effectively inhibited the polymerization of tubulin in vitro, competed with colchicine binding, and disrupted the formation of microtubules in a variety of tumor cell lines, which together showed the molecular target as tubulin. Treatment of MCF-7 breast carcinoma or Jurkat leukemia cells with MPC-6827 led to pronounced G2-M cell cycle arrest followed by apoptosis. Apoptosis, as determined by terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling assay, was preceded by loss of mitochondrial membrane potential, cytochrome c translocation from mitochondria to nuclei, activation of caspase-3, and cleavage of poly(ADP-ribose) polymerase. MPC-6827 was equipotent in an in vitro growth inhibition assay in several cancer cell lines regardless of the expression levels of the multidrug resistance ABC transporters MDR-1 (Pgp-1), MRP-1, and BCRP-1. In B16-F1 allografts and in OVCAR-3, MIAPaCa-2, MCF-7, HT-29, MDA-MB-435, and MX-1 xenografts, statistically significant tumor growth inhibition was observed with MPC-6827. These studies show that MPC-6827 is a microtubule-disrupting agent with potent and broad-spectrum in vitro and in vivo cytotoxic activities and, therefore, MPC-6827 is a promising candidate for development as a novel therapeutic for multiple cancer types. [Cancer Res 2007;67(12):5865–71]

100 项与 EP-128265 相关的药物交易

登录后查看更多信息