• Asian Pacific Journal of Cancer Prevention
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• 제17권3호
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• pp.1103-1110
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• 2016

In the present study, we investigated the effects of motesanib (AMG 706), a multikinase inhibitor alone and in combination with DuP-697, an irreversible selective inhibitor of COX-2, on cell proliferation, angiogenesis, and apoptosis induction in a human colorectal cancer cell line (HT29). Real time cell analysis (RTCA, Xcelligence system) was used to determine the effects on colorectal cancer cell proliferation. Apoptosis was assessed with annexin V staining and angiogenesis was determined with chorioallantoic membrane model. We found that motesanib alone exerted antiproliferative, antiangiogenic and apoptotic effects on HT29 colorectal cancer cells. Combination with DUP-697 increased the antiproliferative, antiangiogenic and apoptotic effects. Results of this study indicate that motesanib may be a good choice in treatment of colorectal tumors. In addition, the increased effects of combination of motesanib with DuP-697 raise the possibility of using lower doses of these drugs and therefore avoid/minimize the dose-dependent side effects generally observed.

• Asian Pacific Journal of Cancer Prevention
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• 제16권16호
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• pp.7089-7095
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• 2015

Clinical evidence shows that dual inhibition of kinases as well angiogenesis provides ideal therapeutic option in the treatment of medullary thyroid carcinoma (MTC) than inhibiting either of these with the events separately. Although treatment with dual inhibitors has shown good clinical responses in patients with MTC, it has been associated with serious side effects. Some inhibitors are active agents for both angiogenesis or kinase activity. Owing to narrow therapeutic window of established inhibitors, the present study aims to identify high affinity dual inhibitors targeting RET and VEGFR2 respectively for kinase and angiogenesis activity. Established inhibitors like Vandetanib, Cabozantinib, Motesanib, PP121, RAF265 and Sunitinib served as query parent compounds for identification of structurally similar compounds by Tanimoto-based similarity searching with a threshold of 95% against the PubChem database. All the parent inhibitors and respective similar compounds were docked against RET and VEGFR2 in order to retrieve high affinity compounds with these two proteins. AGN-PC-0CUK9P PubCID: 59320403 a compound related to PPI21 showed almost equal affinity for RET and VEGFR2 and unlike other screened compounds with no apparent bias for either of the receptors. Further, AGNPC- 0CUK9P demonstrated appreciable interaction with both RET and VEGFR2 and superior kinase activity in addition to showed optimal ADMET properties and pharmacophore features. From our in silico investigation we suggest AGN-PC-0CUK9P as a superior dual inhibitor targeting RET and VEGFR2 with high efficacy which should be proposed for pharmacodynamic and pharmacokinetic studies for improved treatment of MTC.