Selective Nonsteroidal Glucocorticoid Receptor Modulators for the Inhaled Treatment of Pulmonary Diseases

Hemmerling, Martin; Nilsson, Stinabritt; Edman, K. A. P.; Eirefelt, Stefan; Russell, Wayne L.; Hendrickx, Ramon; Johnsson, Eskil; Mårdh, Carina Kärrman; Berger, Markus; Rehwinkel, Hartmut; Abrahamsson, Anna; Dahmén, Jan; Eriksson, Anders; Gabos, Balint; Henriksson, Krister; Hossain, Nafizal; Ivanova, Svetlana; Jansson, Anne-Helene; Jensen, Tina Jellesmark; Jerre, Anders; Johansson, Henrik; Klingstedt, Tomas; Lepistö, Matti; Lindsjö, Martin; Mile, Irene; Nikitidis, Grigorios; Steele, John W.; Tehler, Ulrika; Wissler, Lisa; Hansson, Tiiu

doi:10.1021/acs.jmedchem.7b01215

Cited by 47 publications

(47 citation statements)

References 43 publications

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“…FKB-6 and PPH-5 were modelled based on human FKBP51 (PDB 5NJX) and rat PP5 (PDB 4JA9) respectively 84,85 . For GR-LBD we used the structure solved by Hemmerling et al (PDB 5NFP) 86 . The validity of each crosslinked pair was first confirmed using the algorithm DisVis 87,88 .…”

Section: Molecular Modelling and Docking Calculations A Homology Modmentioning

confidence: 99%

Glucocorticoid receptor complexes form cooperatively with the Hsp90 co-chaperones Pp5 and FKBPs

Kaziales

Barkovits

Marcus

et al. 2020

Sci Rep

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The function of steroid receptors in the cell depends on the chaperone machinery of Hsp90, as Hsp90 primes steroid receptors for hormone binding and transcriptional activation. Several conserved proteins are known to additionally participate in receptor chaperone assemblies, but the regulation of the process is not understood in detail. Also, it is unknown to what extent the contribution of these cofactors is conserved in other eukaryotes. We here examine the reconstituted C. elegans and human chaperone assemblies. We find that the nematode phosphatase PPH-5 and the prolyl isomerase FKB-6 facilitate the formation of glucocorticoid receptor (GR) complexes with Hsp90. Within these complexes, Hsp90 can perform its closing reaction more efficiently. By combining chemical crosslinking and mass spectrometry, we define contact sites within these assemblies. Compared to the nematode Hsp90 system, the human system shows less cooperative client interaction and a stricter requirement for the co-chaperone p23 to complete the closing reaction of GR•Hsp90•Pp5/Fkbp51/ Fkbp52 complexes. In both systems, hormone binding to GR is accelerated by Hsp90 alone and in the presence of its cofactors. our results show that cooperative complex formation and hormone binding patterns are, in many aspects, conserved between the nematode and human systems. Hsp90 is an ATP-driven molecular machine, highly abundant in the cytosol. It is recruited to client proteins that require energy-intense rearrangements and supports these reactions by performing nucleotide-induced conformational changes 1,2. These changes lead to the compaction of the Hsp90 dimer and the transient formation of a ring-like structure, where the N-terminal domains are dimerized in addition to the chaperone's permanent C-terminal dimerization 3. Only in the bacterial Hsp90 system are these changes performed and controlled by Hsp90 itself. In the eukaryotic systems, client-specific cofactors are present, which tailor the Hsp90 machinery into a client-specific mode and regulate the conformational changes while providing further interaction sites for the clients 4. This has been investigated for the Hsp90-dependent maturation of protein kinases with the help of the cofactor Cdc37 and for the chaperoning of steroid receptors, where a larger set of cofactors participates 5-7. Partly, these reactions have been reconstituted with recombinant proteins to identify interaction mechanisms, but mostly addressing the cofactors' interaction with Hsp90 in the absence of clients. Hsp90-containing protein complexes were first identified in the 1980s 8,9. In these studies, steroid hormone receptors, such as the glucocorticoid, mineralocorticoid or progesterone receptors, were isolated from vertebrate cells and the associated proteins were identified and studied by western blot analyses. Hsp90 and several other proteins were detected in these complexes, leading to the identification of Fkbp51, Fkbp52, Cyp40, Hop, p23, Hip and Pp5 as components of steroid hormone receptor complexes 10-14. The gluco...

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Section: Molecular Modelling and Docking Calculations A Homology Modmentioning

confidence: 99%

Glucocorticoid receptor complexes form cooperatively with the Hsp90 co-chaperones Pp5 and FKBPs

Kaziales

Barkovits

Marcus

et al. 2020

Sci Rep

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“…Hemmerling et al [ 97 ] developed a class of potent, nonsteroidal, selective indazole ether-based glucocorticoid receptor modulators (SGRMs) for the treatment of airway inflammation. The authors developed a soft-drug strategy to deliver the first inhaled candidate 166 , which potently inhibited a Sephadex-induced lung edema in a dose-dependent manner with an ED 50 value of 1.2 μg/kg ( Figure 50 ).…”

Section: Biological Applications Of Indazole Derivativesmentioning

confidence: 99%

Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives

2018

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Indazole-containing derivatives represent one of the most important heterocycles in drug molecules. Diversely substituted indazole derivatives bear a variety of functional groups and display versatile biological activities; hence, they have gained considerable attention in the field of medicinal chemistry. This review aims to summarize the recent advances in various methods for the synthesis of indazole derivatives. The current developments in the biological activities of indazole-based compounds are also presented.

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“…The low solubility and slow dissolution rate of AZD7594 enable prolonged lung retention consistent with once-daily administration 1. Lung retention, coupled with low oral bioavailability and a rapid clearance from the systemic circulation, creates a favorable concentration gradient between the lung and the systemic circulation and an opportunity for separation of local and systemic effects 2…”

Section: Introductionmentioning

confidence: 99%

<p>Safety, pharmacokinetics and pharmacodynamics of the selective glucocorticoid receptor modulator AZD7594, following inhalation in healthy Japanese volunteers</p>

Prothon¹,

Tehler²,

Yoon³

et al. 2019

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IntroductionAZD7594 is a non-steroidal, selective, glucocorticoid receptor modulator (SGRM), currently in development for the treatment of asthma and chronic obstructive pulmonary disease. This paper reports a randomized placebo-controlled dose escalation study in healthy Japanese male subjects.MethodsInhaled AZD7594 was administered as one single dose at day 1 (day 1–4), with subsequent multiple daily doses (day 5–16) via a multiple-dose dry powder inhaler for 12 days of once-daily treatment. At each dose level, subjects were randomized to AZD7594 (n=7) or placebo (n=2). The safety, pharmacokinetics (PK) and pharmacodynamics (PD) of AZD7594 were evaluated.ResultsInhaled AZD7594 was safe and well tolerated up to and including the highest dose 1600 µg tested. Plasma exposure suggested dose-proportional PK. The urinary excretion of AZD7594 was negligible (<0.02%). Dose-related effects were observed for 24 hrs plasma cortisol; however, significant cortisol suppression (25%) was only seen at the highest dose level following multiple doses. There were no or only marginal effects on other biomarkers tested (dehydroepiandrosterone sulfate [DHEA-S] and osteocalcin).ConclusionIn conclusion, the early clinical evaluation of inhaled AZD7594 suggests that this novel SGRM is well tolerated in the dose range investigated and also in a Japanese population. It shows dose-proportional plasma exposure, moderate accumulation and has limited impact on systemic markers of glucocorticoid activity.

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Selective Nonsteroidal Glucocorticoid Receptor Modulators for the Inhaled Treatment of Pulmonary Diseases

Cited by 47 publications

References 43 publications

Glucocorticoid receptor complexes form cooperatively with the Hsp90 co-chaperones Pp5 and FKBPs

Glucocorticoid receptor complexes form cooperatively with the Hsp90 co-chaperones Pp5 and FKBPs

Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives

<p>Safety, pharmacokinetics and pharmacodynamics of the selective glucocorticoid receptor modulator AZD7594, following inhalation in healthy Japanese volunteers</p>

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