Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy.
PhD Program in Drug Discovery and Development, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy.
Molecules. 2024 Oct 25;29(21):5051. doi: 10.3390/molecules29215051.
The antiapoptotic BAG3 protein plays a crucial role in cellular proteostasis and it is involved in several signalling pathways governing cell proliferation and survival. Owing to its multimodular structure, it possesses an extensive interactome including the molecular chaperone HSP70 and other specific cellular partners, which make it an eminent factor in several pathologies, particularly in cancer. Despite its potential as a therapeutic target, very few BAG3 modulators have been disclosed so far. Here we describe the identification of a promising BAG3 modulator able to bind the BAG domain of the protein featuring an imidazopyridine scaffold and obtained through the application of the Groebke-Blackburn-Bienaymé chemical synthesis procedure. The disclosed compound showed a relevant cytotoxic activity, and in line with the biological profile of BAG3 disruption, it induced the activation of caspase 3 and 9.
凋亡抑制蛋白 BAG3 在细胞蛋白稳态中发挥着关键作用，并且参与了多个控制细胞增殖和存活的信号通路。由于其具有多结构域的特点，它拥有广泛的相互作用组，包括分子伴侣 HSP70 和其他特定的细胞伴侣，这使得它成为多种病理学，特别是癌症的重要因素。尽管它有作为治疗靶点的潜力，但迄今为止，只有很少的 BAG3 调节剂被披露。在这里，我们描述了一种有前途的 BAG3 调节剂的鉴定，该调节剂能够结合蛋白质的 BAG 结构域，其特征是具有咪唑并吡啶骨架，并通过应用 Groebke-Blackburn-Bienaymé 化学合成程序获得。所披露的化合物表现出相关的细胞毒性活性，并且与 BAG3 破坏的生物学特征一致，它诱导了 caspase 3 和 9 的激活。
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