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

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作者
Linjia Su
Nadezda Bryan
Sabrina Battista
Juliano Freitas
Alyssa Garabedian
Federica D’Alessio
Miriam Romano
Fabiana Falanga
Alfredo Fusco
Lidia Kos
Jeremy Chambers
Francisco Fernandez-Lima
Prem P. Chapagain
Stefan Vasile
Layton Smith
Fenfei Leng
机构
[1] Florida International University,Biomolecular Sciences Institute
[2] Florida International University,Department of Chemistry and Biochemistry
[3] Sanford Burnham Prebys Medical Discovery Institute at Lake Nona,Conrad Prebys Center for Chemical Genomics
[4] CNR,Istituto per l′Endocrinologia e l′Oncologia Sperimentale
[5] Florida International University,Department of Biological Sciences
[6] Università Degli Studi “Federico II” Di Napoli,Dipartimento Di Medicina Molecolare E Biotecnologie Mediche
[7] Florida International University,Department of Environmental Health Sciences
[8] Florida International University,Department of Physics
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摘要
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.
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