Abstract 4624: Molecular target identification of quinolinone based anticancer compounds

• Published in: Cancer research (Chicago, Ill.) Ill.), 2014-10, Vol.74 (19_Supplement), p.4624-4624
• Main Authors: Rylova, Gabriela, Dzubak, Petr, Janostakova, Anna, Frydrych, Ivo, Konecny, Petr, Holub, Dusan, Ozdian, Tomas, Dolezal, Dalibor, Soural, Miroslav, Hlavac, Jan, Hajduch, Marian
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2014-4624

Quinolinones, compounds derived from quinolone antibiotics, are well known for their antibacterial, antiprotozoal, cytotoxic and immunosuppressive effects. Screening of collection of small molecules revealed 2-phenyl-3-hydroxy-4(1H)-quinolinones as molecules with highly selective cytotoxic activity against tumor cell lines. Moreover, in vivo activity assessment of the most active compounds against mouse tumor hollow fibre model of CCRF-CEM cells, showed anticancer activity comparable to doxorubicin. Furthermore, cell biology tests revealed that DNA/RNA synthesis was inhibited together with block of tumor cells in G1 phase within the cell cycle. With these promising results, we decided to continue to identify molecular target and mechanism of action of these compounds and based on such understanding to further improve its biological activity and pharmacological properties. As a first step, the biotinylated molecules of original derivatives were synthesized, which were used for immunoafinity pull down target identification. By mass spectrometry analysis we have reproducibily identified complex of proteins, which are involved in glucose metabolism, translational regulation and are building blocks of cytoskeleton. Involvement of these pathways was further supported by metabolomics, proteomics profiling and by microarray expressional analysis. Identified molecular targets were further validated by western blots, in reporter cell lines and in the cell-free system by measurement of enzymatic activity and monitoring of complex interaction of identified partners, suggesting new mechanisms of regulation. Currently, we are working on the state-of-art proof by structural analysis of target and chinolinone ligand. Acknowledgement: This work was supported by internal grant of Palacky University (LF_2013_016) and BIOMEDREG (CZ.1.05/2.1.00/ 01.0030). Citation Format: Gabriela Rylova, Petr Dzubak, Anna Janostakova, Ivo Frydrych, Petr Konecny, Dusan Holub, Tomas Ozdian, Dalibor Dolezal, Miroslav Soural, Jan Hlavac, Marian Hajduch. Molecular target identification of quinolinone based anticancer compounds. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4624. doi:10.1158/1538-7445.AM2014-4624