Discovery of 7-Hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[<i>b</i>]furan (BNC105), a Tubulin Polymerization Inhibitor with Potent Antiproliferative and Tumor Vascular Disrupting Properties

Flynn, Bernard L.; Gill, Gurmit S.; Grobelny, Damian; Chaplin, Jason H.; Paul, Dharam; Leske, Annabell F.; Lavranos, Tina C.; Chalmers, David K.; Charman, Susan A.; Kostewicz, Edmund; Shackleford, David M.; Morizzi, Julia; Hamel, Ernest; Jung, Mi‐Yeon; Kremmidiotis, Gabriel

doi:10.1021/jm200454y

Cited by 138 publications

(110 citation statements)

References 76 publications

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“…BNC105 is a better clinical candidate due to its dual mode of targeting tumor blood vessels and the tumor itself, and is not susceptible to drug resistance by p-glycoprotein. 8 Furthermore BNC105 demonstrates no toxicity to healthy leukocytes suggesting selectivity toward leukemic cells.…”

Section: Discussionmentioning

confidence: 98%

“…8 Efficacy in response to BNC105P (the clinically used prodrug of BNC105) has been shown in breast and lung cancer xenograft models. 8,9 The firstin-human clinical trial of BNC105P in solid tumors revealed on-target action of the drug with tubulin disruption seen in a surrogate tissue, peripheral blood mononuclear cells (PBMCs). In this study, 4 of 21 patients with advanced and/or metastatic solid tumors achieved stable disease with the single agent.…”

Section: Introductionmentioning

confidence: 99%

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Rapid induction of apoptosis in chronic lymphocytic leukemia cells by the microtubule disrupting agent BNC105

Bates

Feris

Danilov

et al. 2016

Cancer Biology & Therapy

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Microtubule targeting agents, such as vinblastine, are usually thought to arrest cells in mitosis and subsequently induce apoptosis. However, they can also cause rapid induction of apoptosis in a cell-cycle phase independent manner. BNC105 is a novel vascular and microtubule disrupting drug that also induces apoptosis rapidly but with markedly increased potency compared to vinca alkaloids and combretastatin A4. BNC105 binds to the colchicine-binding site on tubulin resulting in activation of c-Jun N-terminal kinase (JNK), phosphorylation of ATF2, and induction of ATF3 and Noxa leading to acute apoptosis in chronic lymphocytic leukemia (CLL) cells. Apoptosis induced by BNC105 is dependent upon both JNK activation and Noxa induction. Normal leukocytes and one CLL sample also exhibited JNK activation but not Noxa induction and were resistant to BNC105. This study emphasizes the importance of Noxa and JNK for induction of apoptosis in CLL cells by microtubule targeting drugs, and highlights the potential of BNC105 as a potent therapeutic to treat haematopoietic malignancies.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Rapid induction of apoptosis in chronic lymphocytic leukemia cells by the microtubule disrupting agent BNC105

Bates

Feris

Danilov

et al. 2016

Cancer Biology & Therapy

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“…administration). 3,29 Pazopanib (Votrient Ò ) was generously provided by GlaxoSmithKline (USA) and prepared in 0.5% hydroxypropylmethylcellulose (HPMC) plus 0.1% Tween80 (both purchased from Sigma-Aldrich) in water.…”

Section: Methodsmentioning

confidence: 99%

The vascular disrupting agent BNC105 potentiates the efficacy of VEGF and mTOR inhibitors in renal and breast cancer

Inglis

Lavranos

Beaumont

et al. 2014

Cancer Biology & Therapy

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Abbreviations: HIF1a, hypoxia-inducible factor 1-alpha; GLUT-1, glucose transporter 1; mTOR, mammalian target of rapamycin; 4EBP1, eukaryotic translation initiation factor 4E binding protein 1; eIF2a, eukaryotic translation initiation factor 2a; VEGF, vascular endothelial growth factor; VDA, vascular disrupting agent; NSCLC, non-small-cell lung carcinoma; PERK, protein kinase-like endoplasmic reticulum kinase; PDGFR, platelet-derived growth factor receptor; TKI, tyrosine kinase inhibitor; PFS, progression free survival; IFNa, interferon a; H&E, hematoxylin and eosin.BNC105 is a tubulin targeting compound that selectively disrupts vasculature within solid tumors. The severe tumor hypoxia and necrosis that ensues translates to short term tumor growth inhibition. We sought to identify the molecular and cellular events activated following BNC105 treatment that drives tumor recovery. We investigated tumor adaptation to BNC105-induced hypoxia in animal models of breast and renal cancer. HIF-1a and GLUT-1 were found to be strongly upregulated by BNC105 as was the VEGF signaling axis. Phosphorylation of mTOR, 4E-BP-1 and elF2a were upregulated, consistent with increased protein synthesis and increased expression of VEGF-A. We sought to investigate the potential therapeutic utility of combining BNC105 with agents targeting VEGF and mTOR signaling. Bevacizumab and pazopanib target the VEGF axis and have been approved for first line use in renal cancer. Everolimus targets mTOR and is currently approved in second line therapy of renal and particular breast cancers. We combined these agents with BNC105 to explore the effects on tumor vasculature, tumor growth inhibition and animal survival. Bevacizumab hindered tumor vascular recovery following BNC105 treatment leading to greater tumor growth inhibition in a breast cancer model. Consistent with this, addition of BNC105 to pazopanib treatment resulted in a significant increase in survival in an orthotopic renal cancer model. Combination treatment of BNC105 with everolimus also increased tumor growth inhibition. BNC105 is currently being evaluated in a randomized phase II clinical trial in combination with everolimus in renal cancer.

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“…The imidazole ring is a widely used template in many drugs. 20 Also the indole group has been investigated in many antitubulin agents, 21 such as 3-formyl-2-phenylindoles, heterocombretastatins, diarylindoles, 2-aroylindoles, D-24851, 2-aryl-3-aroylindoles, 3-aroyl-and 1-aroylindoles, and arylthioindoles. 21 We herein report the evaluation of two classes of nonketone antitubulin agents that contain indole and imidazole moieties.…”

mentioning

confidence: 99%

Structural Optimization of Indole Derivatives Acting at Colchicine Binding Site as Potential Anticancer Agents

Hwang

Wang

et al. 2015

ACS Med. Chem. Lett.

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A new series of indole analogues based on our earlier lead compound, 2-(1H-indol-5-yl)-4-(3,4,5-trimethoxyphenyl)-1H-imidazo[4,5-c]pyridine (42), was prepared as tubulin inhibitors in an effort to find a molecule with improved cytotoxic potency and metabolic stability. A series of indolyl-imidazopyridines (IIP) were synthesized and exhibited potent tubulin polymerization inhibitory activity with potent IC 50 values ranging from 3 to 175 nM against a panel of human melanoma and prostate cancer cell lines. Among these compounds, the 6-indolyl compound 43 showed improved cytotoxic potency (average IC 50 of 9.75 nM vs 55.75 nM) and metabolic stability in human liver microsomes (half-life time was 56.3 min vs. 45.4 min) as compared to previously reported 42. It was also shown to be effective against P-glycoprotein (P-gp) mediated multiple drug resistance (MDR) and taxol resistance.

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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

Cited by 138 publications

References 76 publications

Rapid induction of apoptosis in chronic lymphocytic leukemia cells by the microtubule disrupting agent BNC105

Rapid induction of apoptosis in chronic lymphocytic leukemia cells by the microtubule disrupting agent BNC105

The vascular disrupting agent BNC105 potentiates the efficacy of VEGF and mTOR inhibitors in renal and breast cancer

Structural Optimization of Indole Derivatives Acting at Colchicine Binding Site as Potential Anticancer Agents

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