Abstract
The multidomain BAG3 protein is a member of the BAG (Bcl-2-associated athanogene) family of co-chaperones, involved in a wide range of protein–protein interactions crucial for many key cellular pathways, including autophagy, cytoskeletal dynamics, and apoptosis. Basal expression of BAG3 is elevated in several tumor cell lines, where it promotes cell survival signaling and apoptosis resistance through the interaction with many protein partners. In addition, its role as a key player of several hallmarks of cancer, such as metastasis, angiogenesis, autophagy activation, and apoptosis inhibition, has been established. Due to its involvement in malignant transformation, BAG3 has emerged as a potential and effective biological target to control multiple cancer-related signaling pathways. Recently, by using a multidisciplinary approach we reported the first synthetic BAG3 modulator interfering with its BAG domain (BD), based on a 2,4-thiazolidinedione scaffold and endowed with significant anti-proliferative activity. Here, a further in silico-driven selection of a 2,4-thiazolidinedione-based compound was performed. Thanks to a straightforward synthesis, relevant binding affinity for the BAG3BD domain, and attractive biological activities, this novel generation of compounds is of great interest for the development of further BAG3 binders, as well as for the elucidation of the biological roles of this protein in tumors. Specifically, we found compound 6 as a new BAG3 modulator with a relevant antiproliferative effect on two different cancer cell lines (IC50: A375 = 19.36 μM; HeLa = 18.67 μM).
Highlights
The multimodular BAG3 protein (Bcl-2-associated athanogene 3) is a member of the human BAG family of co-chaperones that interacts, through its conserved BAG domain (BD) located at the C-terminus of the protein, with the ATPase (Adenosine Triphosphatase) domain of heat shock protein 70 (Hsp70), modulating a variety of physiological and pathological functions [1,2,3,4]
BAG3 is over-expressed in several neoplastic cell types and solid tumors including breast cancer, human hepatocellular carcinoma (HCC), glioblastomas, and pancreatic adenocarcinomas, where its high expression levels are correlated with a poor prognosis [8,9,10,11,12,13,14,15,16]
A high level of BAG3 has been detected in the serum of pancreatic ductal adenocarcinoma (PDAC) suffering patients, where it interacts with the transmembrane receptor IFITM-2, located on macrophages surface, producing the inhibition of IL-6 cellular release [17]
Summary
The multimodular BAG3 protein (Bcl-2-associated athanogene 3) is a member of the human BAG family of co-chaperones that interacts, through its conserved BAG domain (BD) located at the C-terminus of the protein, with the ATPase (Adenosine Triphosphatase) domain of heat shock protein 70 (Hsp70), modulating a variety of physiological and pathological functions [1,2,3,4]. A high level of BAG3 has been detected in the serum of pancreatic ductal adenocarcinoma (PDAC) suffering patients, where it interacts with the transmembrane receptor IFITM-2 (interferon-induced transmembrane protein 2), located on macrophages surface, producing the inhibition of IL-6 cellular release [17]. This finding, suggests its relevant role in human diseases linked to macrophages activation, such as inflammatory, cardiac, immune, and degenerative disorders
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