Reference Detail

Ref Type

Journal Article

PMID

(20515948)

Authors

Kremmidiotis G, Leske AF, Lavranos TC, Beaumont D, Gasic J, Hall A, O'Callaghan M, Matthews CA, Flynn B

Title

BNC105: a novel tubulin polymerization inhibitor that selectively disrupts tumor vasculature and displays single-agent antitumor efficacy.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	9	6	2010 Jun	1562-73	Mol Cancer Ther

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
BNC105P	BNC105P	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
BNC105P		BNC 105P\|BNC 105P		BNC105P is a prodrug that upon intracellular conversion to BNC105 selectively inhibits tubulin polymerization, which potentially interferes with tumor vasculature, and may induce tumor cell necrosis and reduce tumor growth (PMID: 20515948).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References