BNC105: a novel tubulin polymerization inhibitor that selectively disrupts tumor vasculature and displays single-agent antitumor efficacy.
Vascular disruption agents (VDA) cause occlusion of tumor vasculature, resulting in hypoxia-driven tumor cell necrosis. Tumor vascular disruption is a therapeutic strategy of great potential; however, VDAs currently under development display a narrow therapeutic margin, with cardiovascular toxicity posing a dose-limiting obstacle. Discovery of new VDAs, which display a wider therapeutic margin, may allow attainment of improved clinical outcomes. To identify such compounds, we used an in vitro selectivity screening approach that exploits the fact that tumor endothelial cells are in a constant state of activation and angiogenesis and do not undergo senescence. Our effort yielded the compound BNC105. This compound acts as a tubulin polymerization inhibitor and displays 80-fold higher potency against endothelial cells that are actively proliferating or are engaged in the formation of in vitro capillaries compared with nonproliferating endothelial cells or endothelium found in stable capillaries. This selectivity was not observed with CA4, a VDA currently under evaluation in phase III clinical trials. BNC105 is more potent and offers a wider therapeutic window. CA4 produces 90% vascular disruption at its no observed adverse event level (NOAEL), whereas BNC105 causes 95% vascular disruption at 1/8th of its NOAEL. Tissue distribution analysis of BNC105 in tumor-bearing mice showed that while the drug is cleared from all tissues 24 hours after administration, it is still present at high concentrations within the solid tumor mass. Furthermore, BNC105 treatment causes tumor regressions with complete tumor clearance in 20% of treated animals.
Kremmidiotis
Gabriel
G
Bionomics Ltd., Thebarton, South Australia, Australia. gkremmid@bionomics.com.au
Leske
Annabell F
AF
Lavranos
Tina C
TC
Beaumont
Donna
D
Gasic
Jelena
J
Hall
Allison
A
O'Callaghan
Michael
M
Matthews
Clayton A
CA
Flynn
Bernard
B
D000818:Animals; D000840:Anisoles / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001572:Benzofurans / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002196:Capillaries / Q000187:drug effects; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D022081:Cell Surface Extensions / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D012074:Remission Induction; D016896:Treatment Outcome; D050257:Tubulin Modulators / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D000840:Anisoles; D000970:Antineoplastic Agents; C552092:BNC 105; D001572:Benzofurans; D050257:Tubulin Modulators