School of Biological Sciences, Nanyang Technological University, Singapore City, Singapore.
Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft, Berlin, Germany.
FEBS Lett. 2023 Aug;597(15):1977-1988. doi: 10.1002/1873-3468.14675. Epub 2023 Jun 8.
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.
构象染色质因子高迁移率族 AT 钩 2（HMGA2）在几种人类恶性肿瘤和病理中起因果作用。HMGA2 在大多数正常成年体细胞中不表达，这使得该蛋白成为一个有吸引力的药物靶点。已建立的基于细胞的化合物文库筛选鉴定出成纤维细胞生长因子受体（FGFR）抑制剂 PD173074 是 HMGA2 介导的转录报告基因激活的拮抗剂。我们确定 PD173074 结合 HMGA2 的 C 末端，并干扰由 C 末端介导的三个 AT 钩 DNA 结合结构域的功能协调。因此，PD173074 对转录激活的 HMGA2 拮抗作用可能是由于 HMGA2 的诱导改变的 DNA 结合模式所致。PD173074 作为一种新型的 HMGA2 特异性拮抗剂，可能会引发具有增强属性和临床潜力的衍生物的开发。
