Pharmacological Exploration of the FK506-Binding Proteins 51 and 52 using PROTACs

使用 PROTAC 对 FK506 结合蛋白 51 和 52 进行药理学探索

• 批准号: 433472263
• 负责人: Professor Dr. Felix Hausch
• 金额: --
• 依托单位: Arbeitsgruppe Strukturbasierte Wirkstoffforschung
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/433472263?language=en
• 关键词: Pharmacological; Exploration; FK506; Binding; Proteins

The FK506-binding protein 51 (FKBP51) and its counterplayer FKBP52 are key regulators of endocrine responses in mammals and are potential therapeutic targets for stress-related disorder, metabolic diseases, hormone-related cancers, and chronic pain. Recently, we developed the first selective inhibitors directed to the FK506-binding site of FKBP51, which have substantially increased our understanding of FKBP51. However, selective pharmacological tools for FKBP52 are still lacking. FKBP51 and FKBP52 are both multi-domain proteins and a key pending biochemical question is, which domains are responsible for the observed (molecular)biological effects (i.e. FK506-binding site vs scaffolding functions of other parts of the proteins).The goal of this chemical-biological project is to synthesize FKBP ligands based on the recently developed PROTAC technology, which allow chemically induced intracellular degradation of FKBP51 or FKBP52 in advanced model systems.(i) The prime objective for FKBP51 is to clarify, which effects of FKBP51 are mediated by the FK506-binding site and which by other parts of the protein. Specifically, we aim to show that FKBP51 degradation, but not inhibition, blocks the effect of FKBP51 on the glucocorticoid receptor (GR), on NF-kB signalling and on the kinase Akt. (ii) For FKBP52, the prime objective is to allow for the first time to pharmacologically differentiate against FKBP51. Specifically, we aim to show that pharmacological manipulation of FKBP52 allows to attenuate neurite outgrowth, GR and AR signaling and prostate cancer cell progression. With FKBP51- and FKBP52-selective probes both in hand, we will specifically explore the interplay between these two proteins. (iii) For the enhancement of PROTAC efficiency, our objective is to stabilize preferred linker conformations by site-specific introduction of methyl side chain substitutions in the oligoethylene glycol backbone. Specifically, we will develop a method for the rapid regio- and stereo-selective synthesis of ethylene/propylene glycol co-oligomers. The results of this proposal will provide fundamentally novel tools to explore human FK506-binding proteins and will clarify important pending questions for FKBP51 and FKBP52. In the PROTAC field, the expected findings would be the so far most compelling evidence that chemically induced protein degradation allows to hit otherwise intractable protein functions. The linker optimization strategy will be a general approach to improve efficacy of functional bioconjugates and of PROTACs in particular.

FK506 结合蛋白 51 (FKBP51) 及其拮抗剂 FKBP52 是哺乳动物内分泌反应的关键调节因子，也是压力相关疾病、代谢疾病、激素相关癌症和慢性疼痛的潜在治疗靶点。最近，我们开发了第一个针对 FKBP51 的 FK506 结合位点的选择性抑制剂，这大大增加了我们对 FKBP51 的了解。然而，仍然缺乏 FKBP52 的选择性药理学工具。 FKBP51 和 FKBP52 都是多结构域蛋白，一个关键的未决生化问题是，哪些结构域负责观察到的（分子）生物效应（即 FK506 结合位点与蛋白质其他部分的支架功能）。该化学生物项目的目标是基于最近开发的 PROTAC 技术合成 FKBP 配体，该技术允许 在高级模型系统中化学诱导 FKBP51 或 FKBP52 的细胞内降解。(i) FKBP51 的主要目标是阐明 FKBP51 的哪些作用是由 FK506 结合位点介导的，哪些是由蛋白质的其他部分介导的。具体来说，我们的目的是证明 FKBP51 降解（而不是抑制）阻断 FKBP51 对糖皮质激素受体 (GR)、NF-kB 信号传导和激酶 Akt 的作用。 (ii) 对于 FKBP52，主要目标是首次在药理学上区分 FKBP51。具体来说，我们的目标是证明 FKBP52 的药理学操作可以减弱神经突生长、GR 和 AR 信号传导以及前列腺癌细胞的进展。有了 FKBP51 和 FKBP52 选择性探针，我们将专门探索这两种蛋白质之间的相互作用。 (iii) 为了提高 PROTAC 效率，我们的目标是通过在寡乙二醇主链中位点特异性引入甲基侧链取代来稳定优选的接头构象。具体来说，我们将开发一种快速区域和立体选择性合成乙二醇/丙二醇共低聚物的方法。该提案的结果将为探索人类 FK506 结合蛋白提供根本性的新颖工具，并将澄清 FKBP51 和 FKBP52 的重要悬而未决的问题。在 PROTAC 领域，预期的发现将是迄今为止最令人信服的证据，证明化学诱导的蛋白质降解可以实现原本难以处理的蛋白质功能。连接子优化策略将成为提高功能性生物共轭物尤其是 PROTAC 功效的通用方法。