MedKoo product information:

 BNC-105

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 of 7-hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan (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.

2: Rischin D, Bibby DC, Chong G, Kremmidiotis G, Leske AF, Matthews CA, Wong SS, Rosen MA, Desai J. Clinical, pharmacodynamic, and pharmacokinetic evaluation of BNC105P: a phase I trial of a novel vascular disrupting agent and inhibitor of cancer cell proliferation. Clin Cancer Res. 2011 Aug 1;17(15):5152-60. Epub 2011 Jun 20. PubMed PMID: 21690571.

3: Kremmidiotis G, Leske AF, Lavranos TC, Beaumont D, Gasic J, Hall A, O'Callaghan M, Matthews CA, Flynn B. BNC105: a novel tubulin polymerization inhibitor that selectively disrupts tumor vasculature and displays single-agent antitumor efficacy. Mol Cancer Ther. 2010 Jun;9(6):1562-73. Epub 2010 Jun 1. PubMed PMID: 20515948.

1. Discovery of 7-Hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan (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.

2. Tubulin biomarker assay for assessing activity of tubulin targeting agents. ByKremmidiotis, Gabriel; Matthews, Clayton Ashley . From PCT Int. Appl. (2011), WO 2011063469 A1 20110603.

3. Combination therapy for treating proliferative diseases. ByKremmidiotis, Gabriel; Leske, Annabell; Lavranos, Tina . From U.S. Pat. Appl. Publ. (2011), US 20110130367 A1 20110602.

4. Combination therapy for treating proliferative diseases. ByKremmidiotis, Gabriel; Leske, Annabell; Lavranos, Tina . From Can. Pat. Appl. (2011), CA 2686587 A1 20110527.

5. Treatment of macular degeneration using a benzofuran-based compound. ByKremmidiotis, Gabriel . From PCT Int. Appl. (2011), WO 2011022781 A1 20110303.

6. Combination therapy with a tubulin polymerization inhibitor and an mTOR inhibitor for treating proliferative diseases. ByKremmidiotis, Gabriel; Bibby, David; Leske, Annabell . From PCT Int. Appl. (2011), WO 2011022772 A1 20110303.

7. BNC105: A Novel Tubulin Polymerization Inhibitor That Selectively Disrupts Tumor Vasculature and Displays Single-Agent Antitumor Efficacy. ByKremmidiotis, Gabriel; Leske, Annabell F.; Lavranos, Tina C.; Beaumont, Donna; Gasic, Jelena; Hall, Allison; O'Callaghan, Michael; Matthews, Clayton A.; Flynn, Bernard . From Molecular Cancer Therapeutics (2010), 9(6), 1562-1573.

8. An Efficient Synthesis and Substitution of 3-Aroyl-2-bromobenzo[b]furans. ByGill, Gurmit S.; Grobelny, Damian W.; Chaplin, Jason H.; Flynn, Bernard L. . From Journal of Organic Chemistry (2008), 73(3), 1131-1134.

9. Substituted benzofurans, benzothiophenes, benzoselenophenes and indoles and their use as tubulin polymerization inhibitors. ByChaplin, Jason Hugh; Gill, Gurmit Singh; Grobelny, Damian Wojciech; Flynn, Bernard Luke; Kremmidiotis, Gabriel . From PCT Int. Appl. (2007), WO 2007087684 A1 20070809. CAPLUS.