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Description of BNC105: BNC105 is a novel compound being developed by Bionomics as a Vascular Disrupting Agent (VDA) for treatment of cancer. VDAs are drugs that disrupt the blood vessels that nourish tumours.
Current developer: Bionomics, Inc.
BNC105 is a novel compound being developed by Bionomics as a Vascular Disrupting Agent (VDA) for treatment of cancer. VDAs are drugs that disrupt the blood vessels that nourish tumours.
BNC105 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. (source: Mol Cancer Ther. 2010 Jun;9(6):1562-73. Epub 2010 Jun 1.)
According to Bonomics's website, BNC105 has several important properties that make it superior to VDAs being developed by other companies: including (1) BNC105 has a higher therapeutic index, meaning that that there is a larger window between its effective dose and the dose at which toxic effects are observed (in mice the therapeutic index for BNC105 is 26 times greater than that for Combretastatin A4 (CA4), another VDA in development). (2) BNC105 has a "dual mode" of operation. In addition to its effect as a VDA, BNC105 has a direct cytotoxic effect upon tumour cells. (3) BNC105 to inhibit tumour growth as a single agent, an effect not seen with combretastatin. It also effectively combines with radiation therapy and with other cytotoxic agents to generate a greater anti-tumour response. (4) BNC105 is selectively retained within tumours.(5) BNC105 does not appear to be affected by the multidrug resistance gene, P-glycoprotein which affects the bioavailability of many anticancer agents by causing secretion of the drug out of cells. (source: http://www.bionomics.com.au/page.php?section=103).
1: Flynn BL, Gill GS, Grobelny DW, Chaplin JH, Paul
D, Leske AF, Lavranos TC, Chalmers DK, Charman SA, Kostewicz E,
Shackleford DM, Morizzi J, Hamel E, Jung MK, Kremmidiotis G. Discovery
(BNC105), a tubulin polymerization inhibitor with potent
antiproliferative and tumor vascular disrupting properties. J Med Chem.
2011 Sep 8;54(17):6014-27. Epub 2011 Aug 5. PubMed PMID: 21774499;
PubMed Central PMCID: PMC3172808.
1. Discovery of
(BNC105), a Tubulin Polymerization Inhibitor with Potent
Antiproliferative and Tumor Vascular Disrupting Properties. ByFlynn,
Bernard L.; Gill, Gurmit S.; Grobelny, Damian W.; Chaplin, Jason H.;
Paul, Dharam; Leske, Annabell F.; Lavranos, Tina C.; Chalmers, David K.;
Charman, Susan A.; Kostewicz, Edmund; et al . From Journal of Medicinal
Chemistry (2011), 54(17), 6014-6027.
(Keyword; CAS#; MedKoo code#)
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