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

靶向实体瘤中的治疗耐药因子 BAG3 和 Bcl-xL

• 批准号: 398347929
• 负责人: Professor Dr. Andreas Brunschweiger
• 金额: --
• 依托单位: Institut für Pharmazie und Lebensmittelchemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/398347929?language=en
• 关键词: Targeting; therapy; resistance; factors; BAG3

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.

Hsp 70共伴侣蛋白和抗凋亡蛋白BAG 3调节癌症的几个关键标志，包括细胞存活、细胞粘附和转移。BAG 3表达在各种实体瘤中升高，在人乳腺癌的原发性肿瘤样品中观察到特别强烈的过表达。促进其抗凋亡功能的一个关键机制是由促生存Bcl-2家族成员（包括Bcl-xL和Mcl-1）的BAG 3依赖性稳定化代表，我们提出BAG 3/ Mcl-1/Bcl-xL轴及其单个组分是克服治疗抗性的有吸引力的靶点。该项目的一个主要目的是剖析BAG 3及其客户蛋白Bcl-xL和Mcl-1在该肿瘤实体中的致癌和抗凋亡功能，以及它们作为药理学靶点的潜力。为此，我们将采用一组不同的耐药性，BAG 3过表达和BAG 3耗尽的细胞模型，结合功能读数，改变信号转导，治疗和凋亡抗性。同时，我们将使用TiDEC（寡胸苷启动的DNA编码化学），一种新开发的策略，用于合成遗传标记的小分子集合（DNA编码库，DEL），合成一个合理设计的DEL，将在Bcl-xL上选择，以确定这种蛋白质的新型抑制剂。候选Bcl-xL抑制剂将另外用于PROTAC（蛋白水解靶向嵌合体）的开发，以在我们的体外癌症模型中通过二聚化诱导的泛素化和蛋白酶体Bcl-xL降解进一步改善靶失活。在一种新的方法中，迄今为止尚未在DEL领域得到证实，我们将使用计算方法基于BAG 3-HSP 70相互作用的结构信息设计DEL，并合成和筛选这种DEL以鉴定这种癌症相关蛋白质-蛋白质相互作用的抑制剂。