In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4397-4397
Abstract:
Chemotherapy and therapy with small targeted molecules are two major strategies for therapy of human cancer at the disseminated stage. During the last decades, thousands of compounds have been developed and, consequently, have improved therapy effectiveness. Especially the development of receptor tyrosine kinase inhibitors such as erlotinib or imatinib were major step forwards in cancer treatment. However, despite its success EGFR inhibitor therapy is still limited by strong side effects, resistance development and insufficient tumor accumulation. Aim of the here presented study was the development of novel EGFR inhibitors, which are specifically activated in the malignant tissue. To this end a cobalt(III)-based prodrug strategy was used, which allows targeted release of the active EGFR inhibitor triggered by hypoxic conditions of the solid tumor. As a first step, new inhibitors with bis-chelating moieties were prepared and tested for their efficacy against several cell models with differing EGFR status. The most promising lead candidate was selected based on potent kinase inhibition (confirmed by in vitro kinase assays as well as Western blotting) resulting in activity against EGFR-driven cells in the nM range (MTT assay). Subsequently, the respective cobalt complex was prepared and its activity tested in hypoxia vs. normoxia revealing that the new complex was distinctly more active under hypoxic conditions. Finally, the anticancer activity of the new complex was tested in two xenografts indicationg potent and hypoxia-dependent anticancer activity also in vivo. Summarizing, cobalt(III)-based tumor-targeting represents a promising strategy to reduce the side effects of tyrosine kinase inhibitors such as erlotinib. Acknowledgements. This work was performed in course of the research platform “Translational Cancer Therapy Research” Vienna, Austria and the COST action CM1105 and supported by “Fonds der Stadt Wien für innovative interdisziplinäre Krebsforschung”. Citation Format: Petra Heffeter, Claudia Karnthaler-Benbakka, Diana Groza, Kushtrim Kryeziu, Walter Berger, Bernhard K. Keppler, Christian R. Kowol. Preclinical development of a novel hypoxia-activated EGFR inhibitor using a cobalt(III)-based prodrug design. [abstract] . In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4397. doi:10.1158/1538-7445.AM2015-4397
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2015-4397
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2015
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
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