Targeting the therapy resistance factors BAG3 und Bcl-xL in solid tumors

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The Hsp70 co-chaperone and anti-apoptotic protein BAG3 regulates several key hallmarks of cancer, including cell survival, cell adhesion and metastasis. BAG3 expression is elevated in various solid tumors with a particularly robust overexpression observed in primary tumor samples of human breast cancer. A key mechanism promoting its antiapoptotic function is represented by BAG3-dependent stabilization of pro-survival Bcl-2 family members including Bcl-xL and Mcl-1 and we propose that the BAG3/ Mcl-1/Bcl-xL axis and its individual components are attractive targets to overcome therapy resistance. One major aim of this project is to dissect the oncogenic and anti-apoptotic functions of BAG3 and its client proteins Bcl-xL and Mcl-1 in this tumor entity, as well as their potential as pharmacological targets. To this end, we will employ a set of different drug-resistant, BAG3-overexpressing and BAG3-depleted cell models in combination with functional readouts for altered signal transduction, therapy- and apoptosis resistance. In parallel, we will use TiDEC (oligoThymidine initiated DNA-Encoded Chemistry), a newly developed strategy for synthesis of genetically tagged small molecule collections (DNA-encoded libraries, DELs), to synthesize a rationally designed DEL that will be selected on Bcl-xL to identify novel inhibitors for this protein. Candidate Bcl-xL inhibitors will additionally be used for the development of PROTACs (proteolysis-targeting chimeras) to further improve target inactivation via dimerization-induced ubiquitination and proteasomal Bcl-xL degradation in our in vitro cancer models. In a new approach, to date not demonstrated in the DEL field, we will use computational methods to design a DEL based on structural information available for the BAG3-HSP70 interaction, and synthesize and screen this DEL to identify inhibitors of this cancer-relevant protein-protein interaction.