CYT997: a novel orally active tubulin polymerization inhibitor with potent cytotoxic and vascular disrupting activity <i>in vitro</i> and <i>in vivo</i>

Burns, Christopher J.; Fantino, Emmanuelle; Phillips, Ian D.; Su, Stephen; Harte, Michael F.; Bukczynska, Patricia; Frazzetto, Mark; Joffe, Max E.; Kruszelnicki, Irma; Wang, Bing; Wang, Yue; Wilson, Neil; Dilley, Rodney J.; Wan, Soo San; Charman, Susan A.; Shackleford, David M.; Fida, Rosa; Malcontenti‐Wilson, Caterina; Wilks, Andrew F.

doi:10.1158/1535-7163.mct-09-0076

Cited by 30 publications

(27 citation statements)

References 27 publications

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“…The collected data for CYT997 reported in this article and our earlier work (Burns et al, 2009a) clearly demonstrate that the compound has significant effects on endothelial cells grown in culture and profound vascular disrupting activity in vivo. The effects parallel those reported for CA4P and other VDAs, and it is likely that the biochemical mechanisms underlying the antivascular effects are similar.…”

Section: Discussionsupporting

confidence: 62%

“…CYT997 is a structurally novel, orally active VDA discovered in our laboratories (Burns et al, 2009b), which has successfully completed two phase I clinical trials (Francesconi et al, 2009;Lickliter et al, 2010). Preliminary antivascular activity of the compound has been reported (Burns et al, 2009a), and in this article we have described further studies to better understand the vascular disrupting effects of the compound with particular regard to dose and functional activity in in vivo tumor models.…”

Section: Discussionmentioning

confidence: 96%

“…We have reported previously the discovery (Burns et al, 2009b) and preliminary biological characterization (Burns et al, 2009a) of (S)-1-ethyl-3-(2-methoxy-4-(5-methyl-4-((1-(pyridin-3-yl)butyl)amino)pyrimidin-2-yl)phenyl)urea (CYT997), a novel synthetic microtubule depolymerizing compound first synthesized in our laboratories. The compound inhibits the polymerization of tubulin with an IC 50 of ϳ3 M and possesses potent cytotoxic activity against a panel of cancer cell lines.…”

Section: (2s)-2-amino-3-hydroxy-n-[2-methoxy-5-[(z)-2-(345-trimetmentioning

confidence: 99%

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The Microtubule Depolymerizing Agent CYT997 Causes Extensive Ablation of Tumor Vasculature In Vivo

Burns¹,

Fantino²,

Powell³

et al. 2011

J Pharmacol Exp Ther

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The orally active microtubule-disrupting agent (S)-1-ethyl-3-(2-methoxy-4-(5-methyl-4-((1-(pyridin-3-yl)butyl)amino)pyrimidin-2-yl)phenyl)urea (CYT997), reported previously by us (Bioorg Med Chem Lett 19:4639 -4642, 2009; Mol Cancer Ther 8:3036 -3045, 2009), is potently cytotoxic to a variety of cancer cell lines in vitro and shows antitumor activity in vivo. In addition to its cytotoxic activity, CYT997 possesses antivascular effects on tumor vasculature. To further characterize the vascular disrupting activity of CYT997 in terms of dose and temporal effects, we studied the activity of the compound on endothelial cells in vitro and on tumor blood flow in vivo by using a variety of techniques. In vitro, CYT997 is shown to potently inhibit the proliferation of vascular endothelial growth factor-stimulated human umbilical vein endothelial cells (IC 50 3.7 Ϯ 1.8 nM) and cause significant morphological changes at 100 nM, including membrane blebbing. Using the method of corrosion casting visualized with scanning electron microscopy, a single dose of CYT997 (7.5 mg/kg i.p.) in a metastatic cancer model was shown to cause destruction of tumor microvasculature in metastatic lesions. Furthermore, repeat dosing of CYT997 at 10 mg/kg and above (intraperitoneally, b.i.d.) was shown to effectively inhibit development of liver metastases. The time and dose dependence of the antivascular effects were studied in a DLD-1 colon adenocarcinoma xenograft model using the fluorescent dye Hoechst 33342. CYT997 demonstrated rapid and dose-dependent vascular shutdown, which persists for more than 24 h after a single oral dose. Together, the data demonstrate that CYT997 possesses potent antivascular activity and support continuing development of this promising compound.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 96%

Section: (2s)-2-amino-3-hydroxy-n-[2-methoxy-5-[(z)-2-(345-trimetmentioning

confidence: 99%

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The Microtubule Depolymerizing Agent CYT997 Causes Extensive Ablation of Tumor Vasculature In Vivo

Burns¹,

Fantino²,

Powell³

et al. 2011

J Pharmacol Exp Ther

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“…However, the largest group of small-molecule VDAs is made up of tubulin binding agents, which target tumor endothelial cells by exploiting their dependence on the tubulin cytoskeleton to maintain cell shape and vascular integrity. All are structurally related to colchicine and include combretastatin A-4 (CA4), its prodrug CA4 phosphate (CA4P), the CA4P analog butyl]amino]-2-pyrimidinyl]phenyl]urea (CYT997) (Thorpe, 2004;Shi and Siemann, 2005;Tozer et al, 2005;Burns et al, 2009;McKeage and Baguley, 2010;Mita et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

The Vascular Disrupting Agent STA-9584 Exhibits Potent Antitumor Activity by Selectively Targeting Microvasculature at Both the Center and Periphery of Tumors

Foley

Zhou

Borella

et al. 2012

J Pharmacol Exp Ther

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Vascular disrupting agents (VDAs) are an emerging class of therapeutics targeting the existing vascular network of solid tumors. However, their clinical progression has been hampered because of limited single-agent efficacy, primarily caused by the persistence of surviving cells at the well perfused "viable rim" of tumors, which allows rapid tumor regrowth to occur. In addition, off-target adverse events, including cardiovascular toxicities, underscore a need for compounds with improved safety profiles. Here, we characterize the mechanism of action, antitumor efficacy, and cardiovascular safety profile of (S)-2-amino-N-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenyl)-3-phenylpropanamide hydrochloride (STA-9584), a novel tubulin-binding VDA. In vitro, 2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)aniline (STA-9122) (active metabolite of STA-9584) displayed increased potency relative to other tubulin-binding agents and was highly cytotoxic to tumor cells. STA-9584 induced significant tumor regressions in prostate and breast xenograft models in vivo and, in an aggressive syngeneic model, demonstrated superior tumor growth inhibition and a positive therapeutic index relative to combretastatin A-4 phosphate (CA4P). It is noteworthy that histological analysis revealed that STA-9584 disrupted microvasculature at both the center and periphery of tumors. Compared with CA4P, STA-9584 induced a 73% increase in central necrotic area, 77% decrease in microvasculature, and 7-fold increase in tumor cell apoptosis in the remaining viable rim 24 h posttreatment. Ultrasound imaging confirmed that STA-9584 rapidly and efficiently blocked blood flow in highly perfused tumor regions. Moreover, cardiovascular effects were evaluated in the Langendorff assay and telemetered dogs, and cardiovascular toxicity was not predicted to be dose-limiting. This bioactivity profile distinguishes STA-9584 from the combretastatin class and identifies the compound as a promising new therapeutic VDA candidate.

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“…CYT997 is a small molecule, orally bioavailable, tubulin polymerisation inhibitor [10][11][12] that has previously been shown by in vitro studies with MDR + cell lines and MDR inhibitors to not be modulated by the MDR phenotype [10]. In addition to efficacy against MDR + cell lines another important attribute of CYT997 is that is can be administered orally [11], unlike many other MTAs. Our data demonstrate that CYT997 inhibited MM cell proliferation, induced cell cycle arrest and apoptosis and synergised with bortezomib in killing MM cells.…”

Section: Introductionmentioning

confidence: 99%

CYT997 Causes apoptosis in human multiple myeloma

Monaghan¹,

Khong²,

Smith³

et al. 2009

Invest New Drugs

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Multiple Myeloma (MM) is an incurable malignancy of mature plasma cells. Microtubule targeting agents (MTAs) are an established class of drug that include many conventional and some novel compounds. MTAs function by inhibiting the polymerisation or depolymerisation of microtubules (MTs) within the cell, disrupting various important cellular functions. We have investigated pre-clinically the novel tubulin polymerisation inhibitor CYT997 for the potential treatment of MM. Here we demonstrate the promising anti-myeloma activity of CYT997 as evidenced by tubulin disruption, inhibition of growth and proliferation, cell cycle arrest and most importantly apoptosis of both human myeloma cell lines (HMCLs) and primary MM cells using nanomolar drug concentrations. CYT997 also synergises with bortezomib to produce more potent anti-MM activity. These in vitro observations were validated in vivo by the ability of CYT997 to significantly prolong survival in a murine model of aggressive systemic myelomatosis. These findings provide a basis for continuing pre-clinical and clinical investigations into the anti-MM effects of CYT997.

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CYT997: a novel orally active tubulin polymerization inhibitor with potent cytotoxic and vascular disrupting activity in vitro and in vivo

Cited by 30 publications

References 27 publications

The Microtubule Depolymerizing Agent CYT997 Causes Extensive Ablation of Tumor Vasculature In Vivo

The Microtubule Depolymerizing Agent CYT997 Causes Extensive Ablation of Tumor Vasculature In Vivo

The Vascular Disrupting Agent STA-9584 Exhibits Potent Antitumor Activity by Selectively Targeting Microvasculature at Both the Center and Periphery of Tumors

CYT997 Causes apoptosis in human multiple myeloma

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