New Thalidomide-Resembling Dicarboximides Target ABC50 Protein and Show Antileukemic and Immunomodulatory Activities

We identified novel dicarboximides that were selectively cytotoxic towards human leukemia cells. Using chemical and biological methods, we characterized the biological activity, identified cellular protein targets and defined the mechanism of action of the test dicarboximides. The reported IC values...

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Bibliographic Details
Published in:Biomolecules (Basel, Switzerland) Switzerland), 2019-09, Vol.9 (9), p.446
Main Authors: Cieślak, Marcin, Kaźmierczak-Barańska, Julia, Królewska-Golińska, Karolina, Napiórkowska, Mariola, Stukan, Iga, Wojda, Urszula, Nawrot, Barbara
Format: Article
Language:English
Subjects:
ABC50 (ABCf1)
anticancer compounds
apoptosis
cytotoxicity
dicarboximides
leukemia
protac (proteolysis targeting chimera)
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Summary:We identified novel dicarboximides that were selectively cytotoxic towards human leukemia cells. Using chemical and biological methods, we characterized the biological activity, identified cellular protein targets and defined the mechanism of action of the test dicarboximides. The reported IC values (concentration required to reduce cell survival fraction to 50% of control) of selected dicarboximides were similar or lower than IC of registered anticancer drugs, for example cytarabine, sorafenib, irinotecan. Test compounds induced apoptosis in chronic myelogenous (K562) and acute lymphoblastic (MOLT-4) leukemia cells by activation of receptor and mitochondrial apoptotic pathways and increased the expression of proapoptotic genes ( . Selected dicarboximides displayed immunomodulatory activity and downregulated IKZF1 and IKZF3 transcription factors in K562 and MOLT-4 leukemia cells. ATP-binding cassette protein 50 (ABC50) was identified as a target for dicarboximides. Cancer cells with knocked down ABC50 showed increased resistance to dicarboximides. Based on the structure of dicarboximides and thalidomide, novel proteolysis-targeting chimeras (PROTACs) were synthesized and used as tools to downregulate ABC50 in leukemia cells.
ISSN:2218-273X
2218-273X
DOI:10.3390/biom9090446