RT Journal Article
SR Electronic
T1 Suramin potently inhibits binding of the mammalian high mobility group protein AT-hook 2 to DNA
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 838656
DO 10.1101/838656
A1 Linjia Su
A1 Nadezda Bryan
A1 Sabrina Battista
A1 Juliano Freitas
A1 Alyssa Garabedian
A1 Federica D’Alessio
A1 Miriam Romano
A1 Fabiana Falanga
A1 Alfredo Fusco
A1 Lidia Kos
A1 Jeremy Chambers
A1 Francisco Fernandez-Lima
A1 Prem P. Chapagain
A1 Stefan Vasile
A1 Layton Smith
A1 Fenfei Leng
YR 2019
UL http://biorxiv.org/content/early/2019/11/12/838656.abstract
AB The mammalian high mobility group protein AT-hook 2 (HMGA2) is a multi-functional DNA-binding protein which 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 high throughput screening (HTS) assay to identify inhibitors targeting HMGA2-DNA interactions. After screening the LOPAC1280 compound library, we discovered that suramin, a negatively charged antiparasitic drug potently inhibits the HMGA2-DNA interaction. Our results also show that the inhibition is through suramin binding to the AT-hooks of HMGA2, therefore blocking its DNA binding capacity. Furthermore, we demonstrate that suramin can induce brain tumor stem cells differentiation into cells with neurite-like structures, a process triggered by disrupting HMGA2-DNA interactions. Since suramin has strong antitumor and anti-metastasis activities, our discovery suggests that HMGA2 and HMGA2-like proteins may be the cellular target of this century-old drug.