The FGFR inhibitor PD173074 binds to the C-terminus of oncofetal HMGA2 and modulates its DNA-binding and transcriptional activation functions

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Item Type:	Article
Title:	The FGFR inhibitor PD173074 binds to the C-terminus of oncofetal HMGA2 and modulates its DNA-binding and transcriptional activation functions
Creators Name:	Ahmed, S.M., Ragunathan, P., Shin, J., Peter, S., Kleissle, S., Neuenschwander, M., Schäfer, R., von Kries, J.P., Grüber, G. and Dröge, P.
Abstract:	The architectural chromatin factor high-mobility group AT-hook 2 (HMGA2) is causally involved in several human malignancies and pathologies. HMGA2 is not expressed in most normal adult somatic cells, which renders the protein an attractive drug target. An established cell-based compound library screen identified the fibroblast growth factor receptor (FGFR) inhibitor PD173074 as an antagonist of HMGA2-mediated transcriptional reporter gene activation. We determined that PD173074 binds the C-terminus of HMGA2 and interferes with functional coordination of the three AT-hook DNA-binding domains mediated by the C-terminus. The HMGA2-antagonistic effect of PD173074 on transcriptional activation may therefore result from an induced altered DNA-binding mode of HMGA2. PD173074 as a novel HMGA2-specific antagonist could trigger the development of derivates with enhanced attributes and clinical potential.
Keywords:	HMGA2, Small Molecule Antagonist, FGFR Inhibitor, PD173074, Chromatin Architectural Factor, Transcriptional Regulator, AT-Hook Domain, C-Terminal Domain
Source:	FEBS Letters
ISSN:	0014-5793
Publisher:	Elsevier
Volume:	597
Number:	15
Page Range:	1977-1988
Date:	August 2023
Official Publication:	https://doi.org/10.1002/1873-3468.14675
PubMed:	View item in PubMed

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