Research Papers:

Targeting of the breast cancer microenvironment with a potent and linkable oxindole based antiangiogenic small molecule

Orestis Argyros, Theodoros Karampelas, Aimilia Varela, Xenophon Asvos, Athanasios Papakyriakou, Adamantia Agalou, Dimitris Beis, Constantinos H. Davos, Demosthenes Fokas and Constantin Tamvakopoulos _

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Oncotarget. 2017; 8:37250-37262. https://doi.org/10.18632/oncotarget.16763

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Orestis Argyros1, Theodoros Karampelas1, Aimilia Varela2, Xenophon Asvos3, Athanasios Papakyriakou4, Adamantia Agalou5, Dimitris Beis5, Constantinos H. Davos2, Demosthenes Fokas3, Constantin Tamvakopoulos1

1Division of Pharmacology-Pharmacotechnology, Biomedical Research Foundation Academy of Athens, Athens, 11527, Greece

2Cardiovascular Research Laboratory, Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation Academy of Athens, Athens, 11527, Greece

3Laboratory of Medicinal Chemistry, Department of Materials Science and Engineering, University of Ioannina, Ioannina, 45110, Greece

4Laboratory of Chemical Biology of Natural Products and Designed Molecules, Institute of Physical Chemistry, N.C.S.R “Demokritos”, Athens, 15310, Greece

5Developmental Biology, Biomedical Research Foundation Academy of Athens, Athens, 11527, Greece

Correspondence to:

Constantin Tamvakopoulos, email: [email protected]

Demosthenes Fokas, email: [email protected]

Keywords: angiogenesis, sunitinib analogue, tumor targeting, breast cancer, tumor microenvironment

Received: June 29, 2016     Accepted: March 22, 2017     Published: March 31, 2017


The clinical efficacy of antiangiogenic small molecules (e.g., sunitinib) in breast carcinoma has largely failed with substantial off-target toxicity. We rationally designed and evaluated preclinically a novel sunitinib analogue, SAP, with favourable pharmacological properties and the ability to be readily conjugated to a targeting peptide or antibody for active tumour targeting.

SAP was evaluated in silico and in vitro in order to verify target engagement (e.g., VEGFR2). Pharmacokinetic and biodistribution parameters were determined in mice using LC-MS/MS. SAP efficacy was tested in two breast cancer xenograft and two syngeneic animal models and pharmacodynamic evaluation was accomplished using phosphokinase assays and immunohistochemistry. Cardiac and blood toxicity of SAP were also monitored.

SAP retained the antiangiogenic and cytotoxic properties of the parental molecule with an increased blood exposure and tumor accumulation compared to sunitinib. SAP proved efficacious in all animal models. Tumors from SAP treated animals had significantly decreased Ki-67 and CD31 markers and reduced levels of phosphorylated AKT, ERK and S6 compared to vehicle treated animals. In mice dosed with SAP there was negligible hematotoxicity, while cardiac function measurements showed a reduction in the percentage left ventricular fractional shortening compared to vehicle treated animals.

In conclusion, SAP is a novel rationally designed conjugatable small antiangiogenic molecule, efficacious in preclinical models of breast cancer.

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