AbstractThe FK506 binding protein 51 (FKBP51) is an appealing drug target due to its role in several diseases such as depression, anxiety, chronic pain and obesity. Towards this, selectivity versus the close homolog FKBP52 is essential. However, currently available FKBP51‐selective ligands such as SAFit2 are too large and lack drug‐like properties. Here, we present a structure activity relationship (SAR) analysis of the pipecolic ester moiety of SAFit1 and SAFit2, which culminated in the discovery of the 1,4‐pyrazolyl derivative 23 d, displaying a binding affinity of 0.077 μM for FKBP51, reduced molecular weight (541.7 g/mol), lower hydrophobicity (cLogP=3.72) and higher ligand efficiency (LE=0.25). Cocrystal structures revealed the importance of the 1,4‐ and 1,3,4‐ substitution patterns of the pyrazole ring versus the 1,4,5 arrangement.

2023-07-14·Cell death discovery

The inhibition of FKBP5 protects β-cell survival under inflammation stress via AKT/FOXO1 signaling.

Article

作者: Wang, Le ; Zhang, Boya ; Song, Xinyao ; Zheng, Rongxiu ; Liu, Tengli ; Cao, Jinglin ; Liang, Rui ; Wang, Shusen ; Li, Rui ; Liu, Na ; Ma, Wenmiao ; Liu, Zewen ; Zou, Jiaqi

The FK506-binding protein 51 (FKBP51, encoded by FKBP5 gene) has emerged as a critical regulator of mammalian endocrine stress responses and as a potential pharmacological target for metabolic disorders, including type 2 diabetes (T2D). However, in β cells, which secrete the only glucose-lowering hormone-insulin, the expression and function of FKBP5 has not been documented. Here, using human pancreatic tissue and primary human islets, we demonstrated the abundant expression of FKBP5 in β cells, which displayed an responsive induction upon acute inflammatory stress mimicked by in vitro treatment with a cocktail of inflammatory cytokines (IL-1β, IFN-γ, and TNF-α). To explore its function, siRNAs targeting FKBP5 and pharmacological inhibitor SAFit2 were applied both in clonal NIT-1 cells and primary human/mice islets. We found that FKBP5 inhibition promoted β-cell survival, improved insulin secretion, and upregulated β-cell functional gene expressions (MAFA and NKX6.1) in acute-inflammation stressed β cells. In primary human and mice islets, which constitutively suffer from inflammation stress during isolation and culture, FKBP5 inhibition also presented decent performance in improving islet function, in accordance with its protective effect against inflammation. Molecular studies found that FKBP5 is an important regulator for FOXO1 phosphorylation at Serine 256, and silencing of FOXO1 abrogated the protective effect of FKBP5 inhibition, suggesting that it is the key downstream effector of FKBP5 in β cells. At last, in situ detection of FKBP5 protein expression on human and mice pancreases revealed a reduction of FKBP5 expression in β cells in human T2D patients, as well as T2D mice model (db/db), which may indicate a FKBP5-inhibition-mediated pro-survival mechanism against the complex stresses in T2D milieus.

2023-07-01·Neuropsychopharmacology

FKBP5 inhibitors modulate alcohol drinking and trauma-related behaviors in a model of comorbid post-traumatic stress and alcohol use disorder

Article

作者: Fain, Katie ; Cruz, Bryan ; Crawford, Meg ; Hirsch, Shawn ; Zorrilla, Eric P ; Xu, Joy C ; Carper, Benjamin A ; Bradley, Lauren ; Kosten, Thomas R ; Roberto, Marisa ; Kirson, Dean ; Nolen, Tracy ; Vozella, Valentina

Post-traumatic stress disorder (PTSD) leads to enhanced alcohol drinking and development of alcohol use disorder (AUD). Identifying shared neural mechanisms might help discover new therapies for PTSD/AUD. Here, we employed a rat model of comorbid PTSD/AUD to evaluate compounds that inhibit FK506-binding protein 51 (FKBP5), a co-chaperone modulator of glucocorticoid receptors implicated in stress-related disorders. Male and female rats received a familiar avoidance-based shock stress followed by voluntary alcohol drinking. We then assessed trauma-related behaviors through sleep bout cycles, hyperarousal, fear overgeneralization, and irritability. To evaluate the role of stress and alcohol history on the sensitivity to FKBP5 inhibitors, in two separate studies, we administered two FKBP5 inhibitors, benztropine (Study 1) or SAFit2 (Study 2). FKBP5 inhibitors were administered on the last alcohol drinking session and prior to each trauma-related behavioral assessment. We also measured plasma corticosterone to assess the actions of FKBP5 inhibitors after familiar shock stress and alcohol drinking. Benztropine reduced alcohol preference in stressed males and females, while aggressive bouts were reduced in benztropine-treated stressed females. During hyperarousal, benztropine reduced several startle response outcomes across stressed males and females. Corticosterone was reduced in benztropine-treated stressed males. The selective FKBP5 inhibitor, SAFit2, reduced alcohol drinking in stressed males but not females, with no differences in irritability. Importantly, SAFit2 decreased fear overgeneralization in stressed males and females. SAFit2 also reduced corticosterone across stressed males and females. Neither FKBP5 inhibitor changed sleep bout structure. These findings indicate that FKBP5 inhibitors modulate stress-related alcohol drinking and partially modulate trauma-related behaviors. This work supports the hypothesis that targeting FKBP5 may alleviate PTSD/AUD comorbidity.

项与 SAFit-2 相关的新闻（医药）

2023-07-21

·生物谷

王树森/郑荣秀/梁瑞团队揭示抑制FKBP5提高β细胞功能的新机制

该研究揭示了FKBP5在β细胞中的功能，为SAFit2应用于临床糖尿病治疗提供了理论依据。全球范围内有超过4亿人患有糖尿病及其并发症，对公共卫生造成极大的负担。其中90%以上为2型糖尿病（T2DM），表现为外周胰岛素抵抗和胰岛素分泌不足。更好地了解β细胞功能障碍在T2DM进展中的分子机制，对于开发新的治疗方法来保护β细胞的功能至关重要。近年来的研究表明FKBP5是代谢调节的重要参与者，人体中FKBP5高表达及其单核苷酸多态性与T2DM发病显著相关，但FKBP5在胰岛中的功能尚未见报道。 2023年7月14日，天津市第一中心医院、天津医科大学王树森/郑荣秀/梁瑞团队在 Cell Death Discovery 期刊发表了题为：The inhibition of FKBP5 protects β-cell survival under inflammation stress via AKT/FOXO1 signaling 的研究论文。该研究首次揭示了FKBP5在人胰岛β细胞中表达，并论证了FKBP5在β细胞中的功能。在这项研究中，研究团队证实了FKBP5在人和小鼠胰岛β细胞中表达。敲低FKBP5或者利用FKBP5拮抗剂SAFit2，能够改善β细胞功能基因表达水平，促进葡萄糖刺激的胰岛素分泌水平，揭示了抑制FKBP5对β细胞功能的保护作用。炎症刺激是T2DM发生发展过程中胰岛β细胞不可避免的应激。因此，研究团队进一步利用体外炎症应激模型发现，炎症应激诱导β细胞中FKBP5高表达，而FKBP5拮抗剂SAFit2能够激活β细胞自噬促进炎症应激下β细胞存活，进而提高β细胞功能。综上所述，该研究揭示了FKBP5在β细胞中的功能，为SAFit2应用于临床糖尿病治疗提供了理论依据。

临床结果

2023-07-20

·生物谷

Cell Death Discovery | 王树森/郑荣秀/梁瑞团队揭示抑制FKBP5提高β细胞功能新机制

2023年7月14日，天津市第一中心医院、天津医科大学王树森/郑荣秀/梁瑞团队在Cell Death Discovery上发表了题为 “The inhibition of FKBP5 protects β-cell survival under inflammation stress via AKT/FOXO1 signaling ” 的最新研究成果。该研究首次揭示了FKBP5在人胰岛β细胞中表达，并论证了FKBP5在β细胞中的功能。全球范围内有超过4亿人患有糖尿病及其并发症，对公共卫生造成极大的负担。其中90%以上为2型糖尿病(T2DM)，表现为外周胰岛素抵抗和胰岛素分泌不足。更好地了解β细胞功能障碍在T2DM进展中的分子机制，对于开发新的治疗方法来保护β细胞的功能至关重要。近年来研究表明FKBP5是代谢调节的重要参与者，人体中FKBP5高表达及其单核苷酸多态性与T2DM发病显著相关，但FKBP5在胰岛中的功能尚未见报道。本研究中，研究者证实FKBP5在人和小鼠胰岛β细胞中表达。敲低FKBP5或者利用FKBP5拮抗剂SAFit2,能够改善β细胞功能基因表达水平，促进葡萄糖刺激的胰岛素分泌水平，揭示了抑制FKBP5对β细胞功能的保护作用。炎症刺激是T2DM发生发展过程中胰岛β细胞不可避免的应激。因此，研究者进一步利用体外炎症应激模型发现，炎症应激诱导β细胞中FKBP5高表达，而FKBP5拮抗剂SAFit2能够激活β细胞自噬促进炎症应激下β细胞存活，进而提高β细胞功能。综上所述，该研究揭示了FKBP5在β细胞中的功能，为SAFit2应用于临床糖尿病治疗提供了理论依据。文章链接：https://www.nature.com/articles/s41420-023-01506-x

100 项与 SAFit-2 相关的药物交易

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