>>Mol Cancer Ther. 2004;3:1365-1374
Discovery and mechanism of action of a novel series of apoptosis inducers with potential vascular targeting activity
Shailaja Kasibhatla1, Henriette Gourdeau2, Karen Meerovitch2, John Drewe1, Sanjeeva Reddy1, Ling Qiu1, Hong Zhang1, Frederick Bergeron2, David Bouffard2, Quan Yang2, John Herich1, Serge Lamothe2, Sui Xiong Cai1 and Ben Tseng1
1 Maxim Pharmaceuticals, Inc., San Diego, California and 2 Shire BioChem, Inc., Laval, Quebec, Canada
Requests for reprints: Shailaja Kasibhatla, Maxim Pharmaceuticals, Inc., 6650 Nancy Ridge Drive, San Diego, CA 92121. Phone: 858-202-4042; Fax: 858-202-4000. E-mail: skasibhatla@maxim.com
A novel series of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes was identified as apoptosis-inducing agents through our cell-based apoptosis screening assay. Several analogues from this series, MX-58151, MX-58276, MX-76747, MX-116214, MX-126303, and MX-116407, were synthesized and further characterized. MX-116407, a lead compound from this series, induced apoptosis with an EC50 of 50 nmol/L and inhibited cell growth with a GI50 of 37 nmol/L in T47D breast cancer cells. Treatment of cells with these analogues led to G2-M arrest, cleavage of essential proapoptotic caspase substrates, and induction of nuclear fragmentation. We identified these compounds as tubulin destabilizers with binding site at or close to the colchicine binding site. Compounds in this series were also active in drug-resistant cancer cell lines with a GI50 value for one of the analogues (MX-58151) of 2.5 nmol/L in paclitaxel-resistant, multidrug-resistant MES-SA/DX5 tumor cells. This series of compounds displayed high selectivity against proliferating versus resting cells. Interestingly, these compounds were shown to disrupt preformed endothelial cell capillary tubules in vitro and affect functional vasculature to induce tumor necrosis in vivo and are thus likely to work as tumor vasculature targeting agents. Among these compounds, MX-116407 showed capillary tubule disruption activity in vitro at concentrations well below the cytotoxic dose. In a separate study, we further characterized the antitumor efficacy and pharmacokinetic profile of this series of compounds and identified MX-116407 as a potent apoptosis-inducing agent with apparent activity as tumor vasculature targeting agent. <<
>>Mol Cancer Ther. 2004;3:1375-1384
Antivascular and antitumor evaluation of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes, a novel series of anticancer agents
Henriette Gourdeau1, Lorraine Leblond1, Bettina Hamelin1, Clemence Desputeau1, Kelly Dong1, Irenej Kianicka1, Dominique Custeau1, Chantal Boudreau1, Lilianne Geerts1, Sui-Xiong Cai2, John Drewe2, Denis Labrecque1, Shailaja Kasibhatla2 and Ben Tseng2
1 Shire BioChem, Inc., Laval, Quebec, Canada and 2 Maxim Pharmaceuticals, Inc., San Diego, California
Requests for reprints: Shailaja Kasibhatla, Maxim Pharmaceuticals, Inc., 6650 Nancy Ridge Drive, San Diego, CA 92121. Phone: 858-202-4042; Fax: 858-202-4000. E-mail: skasibhatla@maxim.com
A novel series of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes was identified as potent apoptosis inducers through a cell-based high throughput screening assay. Six compounds from this series, MX-58151, MX-58276, MX-76747, MX-116214, MX-116407, and MX-126303, were further profiled and shown to have potent in vitro cytotoxic activity toward proliferating cells only and to interact with tubulin at the colchicine-binding site, thereby inhibiting tubulin polymerization and leading to cell cycle arrest and apoptosis. Furthermore, these compounds were shown to disrupt newly formed capillary tubes in vitro at low nanomolar concentrations. These data suggested that the compounds might have vascular targeting activity. In this study, we have evaluated the ability of these compounds to disrupt tumor vasculature and to induce tumor necrosis. We investigated the pharmacokinetic and toxicity profiles of all six compounds and examined their ability to induce tumor necrosis. We next examined the antitumor efficacy of a subset of compounds in three different human solid tumor xenografts. In the human lung tumor xenograft (Calu-6), MX-116407 was highly active, producing tumor regressions in all 10 animals. Moreover, MX-116407 significantly enhanced the antitumor activity of cisplatin, resulting in 40% tumor-free animals at time of sacrifice. Our results identify MX-116407 as the lead candidate and strongly support its continued development as a novel anticancer agent for human use.<<
Just stumbled across these.
Cheers, Tuck |
