Abstract
New chimeric inhibitors targeting the epidermal growth factor (EGFR) and histone deacetylases (HDACs) were synthesized and tested for antineoplastic efficiency in solid cancer (prostate and hepatocellular carcinoma) and leukemia/lymphoma cell models. The most promising compounds, 3BrQuin-SAHA and 3ClQuin-SAHA, showed strong inhibition of tumor cell growth at one-digit micromolar concentrations with IC50 values similar to or lower than those of clinically established reference compounds SAHA and gefitinib. Target-specific EGFR and HDAC inhibition was demonstrated in cell-free kinase assays and Western blot analyses, while unspecific cytotoxic effects could not be observed in LDH release measurements. Proapoptotic formation of reactive oxygen species and caspase-3 activity induction in PCa and HCC cell lines DU145 and Hep-G2 seem to be further aspects of the modes of action. Antiangiogenic potency was recognized after applying the chimeric inhibitors on strongly vascularized chorioallantoic membranes of fertilized chicken eggs (CAM assay). The novel combination of two drug pharmacophores against the EGFR and HDACs in one single molecule was shown to have pronounced antineoplastic effects on tumor growth in both solid and leukemia/lymphoma cell models. The promising results merit further investigations to further decipher the underlying modes of action of the novel chimeric inhibitors and their suitability for new clinical approaches in tumor treatment.
Highlights
IntroductionA plethora of novel approaches for the treatment of advanced cancers has been developed
In the last decades, a plethora of novel approaches for the treatment of advanced cancers has been developed
We report on the synthesis and biological evaluation of novel chimeric inhibitors which consist of newly designed tyrphostin derivates functioning as epidermal growth factor inhibitors coupled with an Histone deacetylases (HDACs)-targeting hydroxamic acid moiety
Summary
A plethora of novel approaches for the treatment of advanced cancers has been developed. The concept of co-inhibiting distinct cellular tumor targets by so-called “chimeric inhibitors,” which merge two drug pharmacophores into a single molecule, has become a promising approach [1]. In the development of novel chimeric inhibitors, the hybridization of histone deacetylase inhibitors with receptor tyrosine kinase inhibitory pharmacophores has emerged as a promising anticancer approach [4]. Histone deacetylases (HDACs), which are overexpressed in various cancers, are epigenetic regulators of chromatin condensation and decondensation They have a strong impact on cancer cell proliferation, spreading, and metastasis. There are drawbacks of the clinical application of single HDAC inhibitors, such as intrinsic or acquired drug resistance [4] These may be overcome by merging an HDAC-inhibitory pharmacophore with another tumor-relevant inhibitor. Small molecule inhibitors of the EGFR and its tyrosine kinase activity, such as gefitinib, erlotinib, or lapatinib, are already clinically approved for the treatment of solid cancers [8,9]
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