Identification of HMGA2 inhibitors by AlphaScreen-based ultra-high-throughput screening assays

Autor:	Stefan Vasile, Fenfei Leng, Sabrina Battista, Juliano Freitas, Jeremy W. Chambers, Alyssa Garabedian, Federica D'Alessio, Miriam Romano, Prem P. Chapagain, Linjia Su, Francisco Fernandez-Lima, Alfredo Fusco, Layton H. Smith, Nadezda Bryan, Fabiana Falanga, Lidia Kos
Jazyk:	angličtina
Rok vydání:	2020
Předmět:	Antiparasitic medicine.drug_class Carcinogenesis Suramin Amino Acid Motifs Biophysics lcsh:Medicine Biochemistry Article HMGA2 High-Throughput Screening Assays parasitic diseases medicine Humans HMGA1a Protein lcsh:Science Cancer Multidisciplinary Adipogenesis Binding Sites biology Base Sequence Chemistry Drug discovery HMGA2 Protein Biological techniques lcsh:R Suramin binding DNA HMGA1 Chemical biology DNA-Binding Proteins High-mobility group biology.protein lcsh:Q medicine.drug Biotechnology
Zdroj:	Scientific Reports, Vol 10, Iss 1, Pp 1-14 (2020) Scientific Reports
ISSN:	2045-2322
Popis:	The mammalian high mobility group protein AT-hook 2 (HMGA2) is a multi-functional DNA-binding protein that plays important roles in tumorigenesis and adipogenesis. Previous results showed that HMGA2 is a potential therapeutic target of anticancer and anti-obesity drugs by inhibiting its DNA-binding activities. Here we report the development of a miniaturized, automated AlphaScreen ultra-high-throughput screening assay to identify inhibitors targeting HMGA2-DNA interactions. After screening the LOPAC1280 compound library, we identified several compounds that strongly inhibit HMGA2-DNA interactions including suramin, a century-old, negatively charged antiparasitic drug. Our results show that the inhibition is likely through suramin binding to the “AT-hook” DNA-binding motifs and therefore preventing HMGA2 from binding to the minor groove of AT-rich DNA sequences. Since HMGA1 proteins also carry multiple “AT-hook” DNA-binding motifs, suramin is expected to inhibit HMGA1-DNA interactions as well. Biochemical and biophysical studies show that charge-charge interactions and hydrogen bonding between the suramin sulfonated groups and Arg/Lys residues play critical roles in the binding of suramin to the “AT-hook” DNA-binding motifs. Furthermore, our results suggest that HMGA2 may be one of suramin’s cellular targets.
Databáze:	OpenAIRE
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