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

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. [ABSTRACT FROM AUTHOR]