Mori Mattia, Ghirga Francesca, Amato Beatrice, Secco Luca, Quaglio Deborah, Romeo Isabella, Gambirasi Marta, Bergamo Alberta, Covaceuszach Sonia, Sgarra Riccardo, Botta Bruno, Manfioletti Guidalberto
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena 53100, Italy.
Department of Chemistry and Technology of Drugs, Sapienza-University of Rome, Rome 00185, Italy.
ACS Omega. 2023 Aug 28;8(36):32424-32431. doi: 10.1021/acsomega.3c02043. eCollection 2023 Sep 12.
HMGA proteins are intrinsically disordered (ID) chromatin architectural factors characterized by three DNA binding domains (AT-hooks) that allow them to bind into the DNA minor groove of AT-rich stretches. HMGA are functionally involved in regulating transcription, RNA processing, DNA repair, and chromatin remodeling and dynamics. These proteins are highly expressed and play essential functions during embryonic development. They are almost undetectable in adult tissues but are re-expressed at high levels in all cancers where they are involved in neoplastic transformation and cancer progression. We focused on identifying new small molecules capable of binding into the minor groove of AT-rich DNA sequences that could compete with HMGA for DNA binding and, thus, potentially interfere with their activities. Here, a docking-based virtual screening of a unique high diversity in-house library composed of around 1000 individual natural products identified 16 natural compounds as potential minor groove binders that could inhibit the interaction between HMGA and DNA. To verify the ability of these selected compounds to compete with HMGA proteins, we screened them using electrophoretic mobility shift assays. We identified Sorocein C, a Diels-Alder (D-A)-type adducts, isolated from and with an HMGA/DNA-displacing activity and compared its activity with that of two structurally related compounds, Sorocein A and Sorocein B. All these compounds showed a cytotoxicity effect on cancer cells, suggesting that the Sorocein-structural family may provide new and yet unexplored chemotypes for the development of minor groove binders to be evaluated as anticancer agents.
高迁移率族蛋白A（HMGA）是内在无序（ID）的染色质结构因子，其特征在于三个DNA结合结构域（AT钩），这些结构域使它们能够结合到富含AT序列的DNA小沟中。HMGA在功能上参与调节转录、RNA加工、DNA修复以及染色质重塑和动力学。这些蛋白质在胚胎发育过程中高度表达并发挥重要功能。它们在成人组织中几乎检测不到，但在所有癌症中均高表达，在这些癌症中它们参与肿瘤转化和癌症进展。我们专注于鉴定能够结合到富含AT的DNA序列小沟中的新小分子，这些小分子可以与HMGA竞争DNA结合，从而潜在地干扰它们的活性。在此，对一个由约1000种单个天然产物组成的独特的高多样性内部文库进行基于对接的虚拟筛选，鉴定出16种天然化合物作为潜在的小沟结合剂，它们可以抑制HMGA与DNA之间的相互作用。为了验证这些选定化合物与HMGA蛋白竞争的能力，我们使用电泳迁移率变动分析对它们进行了筛选。我们鉴定出了Sorocein C，一种狄尔斯-阿尔德（D-A）型加合物，从[来源]中分离出来，具有HMGA/DNA置换活性，并将其活性与两种结构相关的化合物Sorocein A和Sorocein B进行了比较。所有这些化合物对癌细胞均显示出细胞毒性作用，这表明Sorocein结构家族可能为开发作为抗癌剂进行评估的小沟结合剂提供新的且尚未探索的化学类型。
