New 3-Aryl-2-(2-thienyl)acrylonitriles with High Activity Against Hepatoma Cells.

Eva Schaller,Lisa Chiara Gosch,Andrea Volkamer,Michael Höpfner,Bernhard Biersack,Detlef Schuppan,Andi Ma,Nils Goehringer,David Schaller,Adrian Klefenz,Leonard Kaps,Rainer Schobert,Bianca Nitzsche

doi:10.3390/ijms22052243

Abstract

New 2-(thien-2-yl)-acrylonitriles with putative kinase inhibitory activity were prepared and tested for their antineoplastic efficacy in hepatoma models. Four out of the 14 derivatives were shown to inhibit hepatoma cell proliferation at (sub-)micromolar concentrations with IC50 values below that of the clinically relevant multikinase inhibitor sorafenib, which served as a reference. Colony formation assays as well as primary in vivo examinations of hepatoma tumors grown on the chorioallantoic membrane of fertilized chicken eggs (CAM assay) confirmed the excellent antineoplastic efficacy of the new derivatives. Their mode of action included an induction of apoptotic capsase-3 activity, while no contribution of unspecific cytotoxic effects was observed in LDH-release measurements. Kinase profiling of cancer relevant protein kinases identified the two 3-aryl-2-(thien-2-yl)acrylonitrile derivatives 1b and 1c as (multi-)kinase inhibitors with a preferential activity against the VEGFR-2 tyrosine kinase. Additional bioinformatic analysis of the VEGFR-2 binding modes by docking and molecular dynamics calculations supported the experimental findings and indicated that the hydroxy group of 1c might be crucial for its distinct inhibitory potency against VEGFR-2. Forthcoming studies will further unveil the underlying mode of action of the promising new derivatives as well as their suitability as an urgently needed novel approach in HCC treatment.

Highlights

IntroductionLiver cancer (hepatoma) can be subdivided into hepatocellular carcinoma (HCC, the prevalent form of hepatoma) and hepatoblastoma (which mainly affects young children) [1,2]
Tyrosine kinase receptors are involved in tumorigenesis; kinase inhibitors show some benefit and, to date, the multikinase inhibitors sorafenib, lenvatinib and regorafenib have been approved for the treatment of HCC [5,6,7]
We present new thienyl-substituted acrylonitriles as highly active compounds against hepatocellular carcinoma cells

Summary

Introduction

Liver cancer (hepatoma) can be subdivided into hepatocellular carcinoma (HCC, the prevalent form of hepatoma) and hepatoblastoma (which mainly affects young children) [1,2]. Treatment is only curative for earlier stages of HCC, and viable options are liver resection, local radio/chemoablation, and transplantation [2,3]. Chemotherapy has limited efficacy in cases of underlying liver cirrhosis, and due to intrinsic chemoresistance of most HCCs [4]. Tyrosine kinase receptors are involved in tumorigenesis; kinase inhibitors show some benefit and, to date, the multikinase inhibitors sorafenib, lenvatinib and regorafenib have been approved for the treatment of HCC [5,6,7]. The overall survival of the majority of HCC patients who are not eligible for curative approaches is unfavorable [8]. New efficient drugs against HCC that may be used in combination therapies are urgently needed

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Results

Conclusion