2. Academic Validation
  3. Identification of HMGA2 inhibitors by AlphaScreen-based ultra-high-throughput screening assays

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

  • Sci Rep. 2020 Nov 2;10(1):18850. doi: 10.1038/s41598-020-75890-0.
Linjia Su 1 2,  Nadezda Bryan 3,  Sabrina Battista 4,  Juliano Freitas 1 5,  Alyssa Garabedian 1 2,  Federica D'Alessio 6,  Miriam Romano 6,  Fabiana Falanga 6,  Alfredo Fusco 6,  Lidia Kos 1 5,  Jeremy Chambers 1 7,  Francisco Fernandez-Lima 1 2,  Prem P Chapagain 1 8,  Stefan Vasile 3,  Layton Smith 3,  Fenfei Leng 9 10
Affiliations

Affiliations

  • 1 Biomolecular Sciences Institute, Florida International University, Miami, FL, 33199, USA.
  • 2 Department of Chemistry and Biochemistry, Florida International University, 11200 SW 8th Street, Miami, FL, 33199, USA.
  • 3 Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL, 32827, USA.
  • 4 Istituto per l'Endocrinologia e l'Oncologia Sperimentale, CNR, Via Pansini 5, 80131, Naples, Italy.
  • 5 Department of Biological Sciences, Florida International University, Miami, FL, 33199, USA.
  • 6 Dipartimento Di Medicina Molecolare E Biotecnologie Mediche, Università Degli Studi "Federico II" Di Napoli, Naples, Italy.
  • 7 Department of Environmental Health Sciences, Florida International University, Miami, FL, 33199, USA.
  • 8 Department of Physics, Florida International University, Miami, FL, 33199, USA.
  • 9 Biomolecular Sciences Institute, Florida International University, Miami, FL, 33199, USA. lengf@fiu.edu.
  • 10 Department of Chemistry and Biochemistry, Florida International University, 11200 SW 8th Street, Miami, FL, 33199, USA. lengf@fiu.edu.
PMID: 33139812 DOI: 10.1038/s41598-020-75890-0
Abstract

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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