Discovery and mechanism of action of a novel series of apoptosis inducers with potential vascular targeting activity.
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.
Kasibhatla
Shailaja
S
Maxim Pharmaceuticals, Inc., 6650 Nancy Ridge Drive, San Diego, CA 92121, USA. skasibhatla@maxim.com
Gourdeau
Henriette
H
Meerovitch
Karen
K
Drewe
John
J
Reddy
Sanjeeva
S
Qiu
Ling
L
Zhang
Hong
H
Bergeron
Frederick
F
Bouffard
David
D
Yang
Quan
Q
Herich
John
J
Lamothe
Serge
S
Cai
Sui Xiong
SX
Tseng
Ben
B
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
D000970:Antineoplastic Agents; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D020169:Caspases