Steroid hormones, their enzymes and receptors: unmeet success in medical history Pre-receptor control of hormone actions, nuclear hormone receptors and their co-modulators
|
|
Converging avenues to optimally exploit well known desired as well as novelly discovered hormone actions in a tissue- and/or cell-type specific manner; i.e. cortisols full range at multiple targets may still be under- appreciated.Steroid hormones influence all aspects of life. The biological effects cortison and sex steroid have been and continue to the foundation of innovative therapies for a variety of diseases. Exploitation and dissociation of desired from undesired effects constitutes a major challenge with pre-receptor control of hormone actions by small molecule drugs opens new avenues for innovative therapeutic concepts. Here it should be noted that there may be an underestimated difference between the actions and functions of endogenous hydrocortisone (cortisol) as compared to synthetic ligands which usually display a quite different profile with respect to their pharmacologic and pharmacokinetic profiles. In fact, cortisol metabolism appears to be a major determinant of the outcome in inflammation and immunity."Up to date enzymes are amongst the most successful drug targets. The targets of the top 100 pharmaceutical drugs are not human genes that directly cause disease, but are key biochemical switches that produce a desirable change in the physiological state of the organism, which in turn alter or abrogate an ongoing disease process. This emphasizes the strategy of identifying key switches in mammalian physiology that can be modulated to provide a therapeutic effect, which is very different from trying to identify human disease genes that may not themselves be amenable to therapeutic intervention...." Nature Reviews Drug Discovery 2003: Vol 2: 38ff Steroid hormones like cortisol control all aspects of life in an essential and non-redundant manner. Targeting hormone actions has resulted in most successful therapeutic strategies in medical history. Yet, based on the increasing knowlegde on the physiological functions and regulatory pathways for steroid hormone actions, the full exploitation of desired hormone effects is to come.Short chain dehydrogenases, that comprise several validated hydroxysteroid dehydrogenases offer unique avenues for innovative therapeutic concepts and cost effective small molecule drugs. Similarly, some nuclear hormone receptors generate promising preclinical and clinical results and add to the list of novel validated drug targets. InnVentis goal is to establish the know-how leadership network on SDR/HSD and hormone action in general, which eventually results in focussed drug development by incorporating internal and external cutting-edge know-how dynamic manner; i.e. InnVentis will remain flexible to adopt to the increasing technology complexity as well as emerging knowledge on SDR/HSD, nuclear steroid hormone biology to stay on top of any developing trend.
A current view of the basic glucocorticoid signaling system. (A) Intracellular GR activation. 11β-HSD1/2 regulates the conversion of the inactive cortisone (white circles) to the active GR ligand cortisol (black circles). After an agonist such as cortisol binds to the cytoplasmic HSP-bound GR, GR (blue rectangles, GRα N-terminal isoforms; beige rectangles, GRβ N-terminal isoforms (GRβ N-terminal isoforms do not bind glucocorticoids) is released from the HSP and translocates into the nucleus. There, as a dimer, GR interacts with DNA target sequences and glucocorticoid response elements (GREs), as well as with nuclear receptor coactivator and other chromatinremodeling complexes and components of the general transcriptional achinery [see (B)]. Alternatively, GR monomers interact with and alter the activity of a host of transcription factors (dark green oval) such as NF-κB, AP1, and STAT5. GR n nucleocytoplasmic shuttling and transcriptional activity are regulated through phosphorylation by p38 MAPK, JNK, ERK, and CDKs as well as through interactions with 14-3-3 proteins and HSPs. Both nuclear and cytoplasmic GR are degraded through the ubiquitin-proteasomal pathway.We hypothesize that there are at least 16 GRα and GRβ monomers and 256 homo- or heterodimers that may participate in intracellular glucocorticoid signaling. (B) GR transcriptional effects. Dynamic, rapid (subsecond) intranuclear protein-protein and
protein-DNA interactions of ligand-bound GRα isoforms with target GREs, nuclear receptor coactivator complexes [p160, p300 (also
known as CREB-binding protein or CBP), and p/CAF (p300/CBP-associated factor)], and other chromatin-remodeling complexes (SWISNF Transcritional science, unravelling cortisol's biological functions and new therapeutic options: Due to a recent analysis, more then 89% of al studies on glucocortidoids functions do not include the endogenous hormone as a control; there the pro-inflammatory potential of endogenous cortisol, via the minalocorticoid receptors had been overlooked for more then 50 years together with other anecdotic reports by Hench and his colleagues. Analysis of data gathered to date under the translational paradigm and criteria to be defined, will allow delineation of innovative uses of exiting compounds, but even more, identify patentable concepts for corticosteroid mimetics with distinct functions or modulators of endogenous cortisol; the time of cortisol is yet to come! Targetting hormone receptors to induce therapeutically desired effects becomes a more and more difficult task; i.e. intracellular pathways are unpresidentedly. Thus, polypharmacology of small molecule drugs creates a major callenge but may actually also allow targetting desirable effects once appropriate compound collections and biomarkers will contrubute to the appreciation of emerging target classes.. Short chain dehydrogenases are an emerging target class, that comprise various well established targets. Short chain dehydrogenases comprise retinol dehydrogenases and hydroxysteroid dehydrogenases, including the hot targets for diabetes type 2 and metabolic syndrom, i.e. pre-receptor control of glucocorticoid action by 11-β-hydroxysteroid dehydrogenases (11-β-HSDs) and bone loss diseases including rheumatoid arthritis. Short chain dehydrogenases and hydroxysteroid dehydrogenases have been validated as exquisitely drugable target. However, enzyme specificity remains a challenge similar with other gene families making a focus on the target family a necessary prerequesite for "selective" inhibitor development. It is prosed that polypharmacologic compound libraries will contribute to delineate the relevant HSDs physiological functions while opportunitstically establishing NCEs with proprietary biological profile. The latter could be exploited in a "opportunistic" manner, if the compounds safety profile merits the translation into clinical develpment. Beyond the human biology short chain dehydrogenases provide targets for an expanding commercial use and include targets for anti-microbials and anti-micotics. Current estimates anticipate more then 60 short chain dehydrogenases within the humen genome; PDB entrees exceed 3000.
In summary, HSDs and related receptors are are ideally suited to apply modern drug discovery technologies and target validation methodologies: The discovery of new 11beta-hydroxysteroid dehydrogenase type 1 inhibitors by common feature pharmacophore modeling and virtual screening. Bioinformatic identification and characterization of new members of short-chain dehydrogenase/reductase superfamily. Compound library development guided by protein structure similarity clustering and natural product structure Cortisol metabolism by 11 beta-hydroxysteroid dehydrogenase as a novel target in the treatment of inflammation- or immune-mediated bone loss: comment on the article by Makrygiannakis et al.
|
|
