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.

FK 506结合蛋白51（FKBP 51）及其对应物FKBP 52是哺乳动物内分泌反应的关键调节因子，是应激相关疾病、代谢疾病、乳腺癌和慢性疼痛的潜在治疗靶点。最近，我们开发了第一个针对FKBP 51的FK 506结合位点的选择性抑制剂，这大大增加了我们对FKBP 51的理解。然而，FKBP 52的选择性药理学工具仍然缺乏。FKBP 51和FKBP 52都是多结构域蛋白，并且关键的未决生物化学问题是，哪些结构域负责观察到的FKBP 51和FKBP 52的功能。（分子）生物学效应（即FK 506结合位点与蛋白质其他部分的支架功能）。该化学-生物学项目的目标是基于最近开发的PROTAC技术合成FKBP配体，其允许在高级模型系统中化学诱导FKBP 51或FKBP 52的细胞内降解。(i)FKBP 51的主要目的是阐明FKBP 51的哪些作用是由FK 506结合位点介导的，哪些作用是由蛋白质的其他部分介导的。具体而言，我们的目的是表明FKBP 51降解，而不是抑制，阻断FKBP 51对糖皮质激素受体（GR），NF-κ B信号传导和激酶Akt的作用。(ii)对于FKBP 52，主要目标是首次允许与FKBP 51完全区分。具体来说，我们的目的是表明，药理学操纵FKBP 52允许衰减神经突生长，GR和AR信号和前列腺癌细胞的进展。有了FKBP 51和FKBP 52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的效率，我们的目标是通过在寡聚乙二醇骨架中位点特异性引入甲基侧链取代来稳定优选的接头构象。具体而言，我们将开发一种方法，用于快速区域和立体选择性合成的乙二醇/丙二醇共低聚物。该提案的结果将为探索人类FK 506结合蛋白提供全新的工具，并将澄清FKBP 51和FKBP 52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，表明化学诱导的蛋白质降解可以打击其他棘手的蛋白质功能。接头优化策略将是提高功能性生物缀合物和特别是PROTAC的功效的一般方法。