Pii: s0006-2952(02)01121-8

Biochemical Pharmacology 64 (2002) 355±361 Department of Molecular and Cellular Biology, Ligand Pharmaceuticals, 10275 Science Center Drive, San Diego, CA 92121, USA Glucocorticoids are the most effective anti-in¯ammatory agents known. However,the use of these powerful molecules is plagued by a host of serious,sometimes life-threatening side-effects. The search for new compounds that maintain the ef®cacy of the steroids without some of the side-effects has entered a new phase. New approaches are leading to novel kinds of steroidal and non-steroidal compounds with unique pro®les that may represent the next generation of safer glucocorticoids.
# 2002 Elsevier Science Inc. All rights reserved.
Keywords: Selective glucocorticoid receptor modulators; Steroid receptor ligand; Non-steroidal anti-in¯ammatory agent nately,early on,it was discovered that these compounds had a severely negative impact on patients to whom they Early efforts to understand endocrine function focused were administered. Efforts from that point on have focused on extracts derived from glands whose removal caused on ®nding molecules that have anti-in¯ammatory ef®cacy speci®c systemic pathologies in animals. The adrenal was equal to that of the steroids,but with a reduction in side- one such gland. Organic extracts from this gland could be effects. Progress has been made with several synthetic used to ameliorate the symptoms of Addison's disease steroidal versions that exhibit increased receptor speci®- (later discovered to be caused by the speci®c lack of the city and potency (dexamethasone) as well as versions for glucocorticoid hormone cortisol). Addison's patients exhi- use in topical,inhaled,or other non-oral formulations.
bit hyperpigmentation of the skin,hypoglycemia,and salt These,typically,are extremely potent steroids with high craving,among other symptoms. These patients do not ef®cacy that are cleared rapidly by ®rst-pass metabolism.
respond effectively to stress,creating the potential for an This pro®le results in excellent ef®cacy at the point of Addisonian crisis,a disease cascade that is potentially life- application (e.g. lung and skin) but with reduced,although threatening. The majority of these symptoms can be elimi- nated with the injection of adrenal extracts.
The isolation of the active components from this gland by Tadeus Reichstein and Edward Kendall,and the sub- sequent use in patients with rheumatoid arthritis by Philip Hench,garnered all three the Nobel Prize in 1950. These Corticosteroids produced in the adrenal gland undergo agents were remarkably effective at inhibiting many forms metabolism into two compounds (glucocorticoids and of in¯ammation and were used at high doses over long mineralocorticoids) with markedly different activities; periods of time,resulting in excellent ef®cacy. Unfortu- glucocorticoids like cortisol have effects on carbohydrate, fat,and protein metabolism,and mineralocorticoids like aldosterone have effects on sodium levels by raising Tel.: ‡1-858-550-7807; fax: ‡1-858-550-7235.
reabsorption in the kidney The responses to these E-mail address: jminer@ligand.com (J.N. Miner).
Abbreviations: CRH,corticotropin-releasing hormone; CRF,corticotro- hormones are mediated by two different intracellular pin-releasing factor; ACTH,adrenocorticotropin hormone; HPA,hypotha- receptors,which are capable of binding to and thereby lamic-pituitary-adrenal; GVHD,graft-versus-host disease; PEPCK, being activated by these steroids,translocating to the phosphoenol pyruvate carboxy kinase; LBD,ligand-binding domain; nucleus,and regulating speci®c target genes. This signal GRIP-1,GR interacting protein 1; NFkB,nuclear factor-kappa B; AP-1, activator protein 1; PPAR,peroxisome proliferator activated receptor; PGC- transduction pathway is unique in that it utilizes a single 1,PPARg coactivator 1; HNF-4,hepatocyte nuclear factor 4.
protein that is both the proximal ligand receptor as well as 0006-2952/02/$ ± see front matter # 2002 Elsevier Science Inc. All rights reserved.
PII: S 0 0 0 6 - 2 9 5 2 ( 0 2 ) 0 1 1 2 1 - 8 J.N. Miner / Biochemical Pharmacology 64 (2002) 355±361 the transcription factor that interacts with DNA in the patients present with a combination of symptoms grouped nucleus. The GR,in particular,is responsible for up- under the heading `Cushing's syndrome' The symp- regulating and down-regulating a wide range of genes toms include central obesity,glucose intolerance,myopa- affecting a number of critical metabolic pathways. Glu- thy,and hypertension,among others. The pathophysiology cocorticoids are commonly known as the stress hormones, of this condition is most often related to dysregulation of and,under normal circumstances,they are crucial to the the system that produces glucocorticoids due to tumors or ability of the body to respond and adapt to stress. Stress other endocrine problems. Certain adrenal tumors are causes signaling within the two key components of the known to secrete large quantities of cortisol and are not stress response,CRH neurons found in the paraventricular regulated by normal feedback mechanisms. Over-secretion nucleus of the hypothalamus and in other areas of the of signaling molecules within the glucocorticoid produc- central nervous system as well as the noradrenergic neu- tion pathway,CRF or ACTH by the pituitary or non- rons of the locus-ceruleus-norepinephrine system. Activa- pituitary cells,can also increase serum levels of cortisol tion of these systems induces psychological,behavioral, and physical changes that provide an adaptive bene®t in the The last and perhaps the most common way in which short term. The HPA axis is on the receiving end of signals imbalances in the stress response system can present from the CRH neurons. This axis is the primary regulator themselves is when patients are administered exogenous of endogenous glucocorticoid production. CRF from CRH neurons acts on the anterior pituitary gland to cause the Glucocorticoids are extremely effective and frequently secretion of ACTH,which,in turn,induces corticosteroid used therapeutic agents that are administered for a wide production and release from the adrenal gland. Thus,in range of disorders. Supplemental glucocorticoids can response to stress,the HPA axis is activated,and gluco- replace cortisol absent in various adrenal insuf®ciency corticoid levels in serum increase. The behavioral and syndromes These compounds are also effective psychological changes that occur when cortisol levels rise anti-in¯ammatory agents for many autoimmune and are indicative of a ®ght or ¯ight response and include in¯ammatory disorders,such as rheumatoid arthritis and increases in alertness,mental acuity,pain tolerance,tem- asthma. With rheumatoid arthritis,treatment with non- perature,and euphoria coupled with decreases in sexual steroidal anti-in¯ammatory drugs (NSAIDs) provides sig- desire,reproductive behavior,and appetite The phy- ni®cant bene®t; however,the progression of the disease sical/physiological changes include increases in respiration eventually demands the use of glucocorticoids. Steroids rate,oxygenation,cardiovascular tone,blood ¯ow,pres- inhibit the signs and symptoms of the in¯ammation asso- sure,and heart rate. Accompanying these are adjustments ciated with rheumatoid arthritis,but fail to reverse any in metabolism to provide glucose and energy by increasing structural damage that has already occurred in the joint.
gluconeogenesis in the liver and lipolysis in fat depots.
Additionally,patients with asthma often use inhaled and Protein is broken down to provide substrates for gluconeo- oral steroids to control exacerbation of their condition.
genesis. A number of peripheral systems unnecessary to the Immunosuppressive therapy for transplant rejection and short-term stress response are inhibited. These suppressed autoimmune disorders often makes use of short-term,high- functions include growth,reproduction,food absorption, dose treatment with steroids followed by more protracted and the immune response. Interestingly,the stress response lower dose treatment to reduce the cell-mediated response also provides an autoregulatory mechanism to reduce the to transplanted foreign tissue. Patients receiving bone production of glucocorticoid after high levels have been marrow transplants occasionally develop acute GVHD.
achieved. This is accomplished by feedback of glucocorti- Glucocorticoids are extremely useful in GVHD; other coids onto the signaling pathways that induce glucocorti- therapeutics are used only for steroid-resistant GVHD coid production. Glucocorticoids inhibit the expression of genes involved in activating the HPA axis,including multiple myeloma and certain lymphomas and leukemias, corticotropin-releasing factor and ACTH,thereby regulat- respond well to combination therapies that include the ing corticosteroid production from the adrenal gland glucocorticoids prednisone or dexamethasone.
There are several situations when this carefully balanced Exposure to high,sustained levels of corticosteroids by system can go awry. Chronic,uncontrolled stress leads to any mechanism uncouples the normal metabolic processes long-term activation of the HPA axis and sustained,high from autoregulatory feedback mechanisms and induces a glucocorticoid levels. Pathological conditions in which stress response physiological state that cannot be main- activation of the HPA axis has been demonstrated include tained long term without severe consequences. The numer- depression,obsessiveÐcompulsive disorder,alcohol and ous side-effects experienced by patients administered drug abuse,and anorexia nervosa The action of steroids over the long term are perhaps the clearest exam- glucocorticoids in response to chronic stress is decidedly ple of this. The response to glucocorticoids is complex,due in large measure to the wide variety of physiological Imbalances in cortisol production can also occur in contexts in which glucocorticoids act . Complications certain conditions that overproduce glucocorticoids. These are time- and dose-dependent and can occur acutely with J.N. Miner / Biochemical Pharmacology 64 (2002) 355±361 very high doses,or more slowly with chronic exposure and the glucose production pathways. While bene®cial in the lower doses. Fortunately,glucocorticoid-regulated clinical short term,this decreases overall muscle function when markers of speci®c side-effects are available from the activated for an extended period of time.
extensive clinical trials conducted over the years with The behavioral effects of glucocorticoids are of great glucocorticoids. These markers are relevant to many of concern to patients. Glucocorticoids have long been known the impacts of glucocorticoids on bone,fat,and carbohy- to have psychogenic effects in a subset of patients when drate metabolism. Most are readily monitored in response given at high doses. Approximately 5% of patients will to short-term exposure to glucocorticoids and include experience some degree of inappropriate euphoria,psy- serum cortisol,a measure of HPA suppression,lipid pro®le chosis,or depression Patients are also quite con- changes,which measure weight effects,serum glucose and cerned with the effects of glucocorticoids on fat insulin levels,a measure of effects on insulin resistance redistribution and weight gain. Fat and muscle are lost and hepatic glucose output,and urinary collagen peptides from limbs,but truncal and visceral areas actually accu- and serum osteocalcin that help assess the impact of mulate fat. Facial,supraclavical,and posterior cervical fat compounds on bone metabolism. Together,these markers depots are particularly sensitive to glucocorticoids,result- can assist in the assessment of speci®c compounds early in ing in the moon face and buffalo hump characteristic of clinical trials. The speci®c side-effects of glucocorticoids long-term glucocorticoid treatment Even one dose of can be ranked by patients and physicians. These vary a glucocorticoid is suf®cient to increase hepatic glucose somewhat depending on the person doing the ranking.
production and increase insulin resistance of peripheral In particular,patients tend to highlight the physical and tissues. The glucocorticoid effect on glycemic control is mental changes that accompany long-term steroid use.
thought to target insulin signaling . Glucocorticoids These include fat redistribution and weight gain and affect insulin-mediated increases in blood ¯ow to muscles steroid-induced psychosis/neurosis. Physicians,on the They decrease key insulin receptor signaling mole- other hand,tend to concentrate on problems that affect cules and increase glucose output by increasing the rate- patient medical care,which include hyperglycemia,gen- limiting enzyme in gluconeogenesis,PEPCK .
eralized insulin resistance,as well as suppression of the Glucocorticoids also inhibit the release of insulin from HPA axis. However,without question,the single most the pancreas,acting directly on the pancreatic b cells. This important side-effect from the standpoint of many physi- action may involve apoptosis of b cell populations,leading cians is osteoporosis. This side-effect alone accounts for an to decreased insulin production as well as more direct enormous amount of morbidity among patients receiving inhibition of insulin expression The molecular glucocorticoids. Long-term glucocorticoid treatment often details underpinning regulation of hepatic glucose produc- results in some degree of osteoporosis in patients. Because tion have been made clearer recently by discoveries linking these patients also suffer from decreased muscle mass as a GR,other transcription factors,and cyclic AMP (cAMP) in consequence of steroid treatment,they are more suscep- tible to falling. The consequences of falls and subsequent fractures become enormous when one considers that many of these patients are already sick with a debilitating dis- ease. A hip fracture late in life with its attendant inactivity and increased potential for pneumonia can have fatal The GR acts as a ligand-regulated transcription factor consequences for elderly patients. Susceptibility to frac- responding to circulating cortisol. It is a member of the tures and aseptic necrosis of the femoral head increases large family of intracellular receptors comprised of both within months of starting glucocorticoid therapy the nuclear hormone receptors as well as the steroid Steroids degrade the quality of trabecular bone,resulting in receptor subfamilies. The protein itself is composed of an increase in fracture rate . Bone loss is highest in the three general domains: a DNA-binding domain,a C-term- ®rst 6 months of therapy,after which patients continue to inal ligand-binding domain (LBD),and an N-terminal lose bone,but at a slower rate. When taken off steroids, activation domain. It is capable of regulating transcription patients do appear to partially regain bone The loss both negatively and positively and is localized to the of muscle compounds the osteoporosis problem. Gluco- cytoplasm in the absence of hormone. The receptor is held corticoid-induced myopathy results in decreased strength in an inactive state poised to bind ligand by interaction with and muscle mass. The mechanism by which glucocorti- a chaperonin complex comprised of heat shock proteins.
coids affect muscle mass is partially due to hypogonadism Upon binding ligand,the receptor undergoes a conforma- observed in many patients with the consequent decline in tional change that dissociates the heat shock proteins and levels of the sex steroids estrogen and testosterone,which activates a number of receptor functions including DNA are responsible for contributing to the maintenance of both binding activity,nuclear localization,and transcriptional muscle and bone mass Furthermore,mimicking a regulation. The latter involves the direct and indirect inter- stress response,muscle is broken down and utilized as a action with a large number of transcription factors critical source of substrates and energy for the increased activity in to gene regulation including RNA polymerase as well J.N. Miner / Biochemical Pharmacology 64 (2002) 355±361 as various polymerase-associated proteins. The complex repression prompted a recent analysis of the collage- that forms at a regulated gene is quite large,and the nase-3 gene promoter under glucocorticoid-repressed con- receptor likely does not contact RNA polymerase directly, ditions Given the previously described role for GRIP-1 but instead utilizes several types of so-called ``coactivator'' as a coactivator,it came as a surprise when these authors proteins to bridge the gap between itself and the polymer- demonstrated an important role for GRIP-1 in repression.
ase The details of the interaction between the receptor They demonstrated that GRIP was recruited to the col- and these coactivators are understood from genetic,bio- lagenase promoter during the act of repression by the GR.
chemical,and crystallographic standpoints for only a few The ligand-dependent recruitment of these proteins might speci®c receptorÐcoactivator pairs. In general,these inter- be used as a readout to detect potentially bene®cial ther- actions make use of the LBD of the receptor,although other less well-characterized interactions clearly occur in The search for a novel glucocorticoid that has the anti- the N-terminal and DNA binding domains Coactiva- in¯ammatory properties of conventional steroids without tors bind to the LBD of the GR in a hormone-dependent one or more of the side-effects has been a long-standing fashion,interacting directly with the extreme C-terminal goal of the ®eld. Much effort has been spent on modifying portion of the LBD. This interaction domain is formed by the steroid backbone to achieve this sort of increased the juxtaposition of several helical segments within the therapeutic index; however,these efforts have met with protein. The interaction surface between these transcrip- little success. De¯azacort,a D-ring-substituted steroid tion factors is comprised of a hydrophobic pocket on the otherwise similar to cortisol,was touted originally as a receptor and a helical sequence containing an LxxLL powerful anti-in¯ammatory molecule exhibiting more amino acid motif on the coactivator This interaction selective,i.e. reduced,activity,in particular on bone and is very sensitive to the structure of the ligand bound in the on glucose metabolism. Initially,clinical data supported pocket. Coactivators typically bind avidly in the presence this notion . However,subsequent trials that adjusted of agonists,but fail to bind in the presence of antagonist the steroid dose to maintain equivalent anti-in¯ammatory ligands. In fact,this is likely the mechanism of antagonist ef®cacy usually needed higher levels of de¯azacort. Unfor- action. This conformational sensitivity is due to the tunately,at these higher doses,the advantages of de¯azacort changes in receptor structure brought about by the structure disappeared The ®eld was re-energized by the dis- of the ligand bound in the pocket. The receptor appears to covery of the likely mechanism of GR-mediated repression actually condense around the ligand during the binding of a wide variety of pro-in¯ammatory genes. The receptor reaction,meaning that structural changes in the ligand are was shown to bind directly to speci®c transcription factors transmitted directly to the receptor and to the receptor (NFkB and AP-1) involved in up-regulating in¯ammatory surfaces that interact with coactivators Thus,ligands genes. This represented a unique mechanism that was can change the ability of the receptor to bind to coactivators.
genetically separable from transcriptional activation. The These coactivators may also play a role in the tissue-speci®c search began for ligands that could induce transcriptional activity of glucocorticoids. Although many coactivators are repression,but hinder transcriptional activation. In 1997, expressed widely,some have been described that exhibit a the ®rst compounds that separated transactivation from restricted tissue expression pattern Coactivators are not only involved in transcriptional activation,but they also These compounds were steroidal in nature,were very appear to play a role in transcriptional repression. Recent ef®cient inhibitors of both AP-1- and NFkB-mediated gene data have demonstrated that transcriptional repression by induction,and were strong anti-in¯ammatory agents in many members of the nuclear hormone receptor family is vivo. They also were reported to have reduced ability to dependent upon speci®c corepressor proteins that bind activate gene expression in some,but not all cellular directly to the receptor in the absence of hormone and contexts. Unfortunately,thus far,no in vivo therapeutic inhibit the transcription process by recruiting histone dea- advantage has been demonstrated for these types of mole- cetylases ,which appear to condense chromatin and cules when side-effects were measured This result therefore repress transcription . However,most mem- calls into question the usefulness of the activation±repres- bers of the steroid receptor subfamily are sequestered in the cytoplasm in the absence of hormone and exhibit gene- We have also pursued this hypothesis as an approach to speci®c repression or activation only when hormone is discovering selective GR modulators. An example of the present. Corepressors have not yet been shown to bind compounds identi®ed during this collaborative effort steroid receptors during normal gene regulation between Ligand Pharmaceuticals and Abbott Laboratories although there is evidence for interaction when bound to is AL-438 (Abbott-Ligand 438),which was shown to be a speci®c,non-steroidal ligand for the GR that exhibited a The ubiquitous coactivator GRIP-1 has been shown to unique pro®le,both in vitro and in vivo. The molecule is bind to GR and other intracellular receptors and to enhance fully ef®cacious at transcriptional repression compared their transcriptional activation activity . Unresolved with prednisolone on certain genes related to the anti- questions regarding the mechanism of steroid receptor in¯ammatory aspects of glucocorticoid activity (E-selectin J.N. Miner / Biochemical Pharmacology 64 (2002) 355±361 and interleukin-6),but is weaker (a partial agonist) for This is consistent with the gene-speci®c activity transcriptional activation. Using other promoters in differ- described earlier. The mechanism may be found in the ent cell backgrounds,AL-438 is more active as a transcrip- fact that AL-438 generates a receptor conformation that tional activator. Thus,AL-438 does not completely differs from steroids,which in turn changes the spectrum of separate transcriptional repression from activation,but coactivators with which the receptor can interact. Certain instead appears to be separating activities in a gene-speci®c coactivators bind GR with identical af®nity in the presence fashion. In animal models,AL-438 was as ef®cacious as of either AL-438 or prednisolone,while others exhibit prednisolone at inhibiting in¯ammation. Importantly,AL- signi®cantly reduced af®nity in the presence of this com- 438 exhibited signi®cantly reduced impact on fasting pound. We believe that since different genes have different glucose levels compared with prednisolone,suggesting requirements for speci®c coactivators,this may be the that this compound might not cause the diabetogenic molecular rationale for AL-438's gene-selective pro®le.
effects of steroidal glucocorticoids.
The coactivator GRIP-1 is an example of a potential An as-yet-unanswered question is whether the improved mediator of gene-speci®c effects,given its demonstrated pro®le of AL-438 in vivo is a direct result of its altered effect involvement in both transcriptional repression and activa- on GR structure and function as detected by in vitro assays.
tion. We have examined the interactions between GRIP-1 It is possible that it is the speci®c conformation of the and GR in a variety of mammalian two-hybrid and GST receptor detected by our in vitro assays that is responsible pull-down assays. Our ®ndings indicate that,in a manner for the therapeutically bene®cial pro®le observed in rodents.
similar to prednisolone,AL-438 will induce the interaction Fig. 1. Selective glucocorticoid receptor modulator (SGRM) coactivator hypothesis. This figure depicts a model that attempts to distinguish the effects of steroidal glucocorticoids from SGRMs. Both compounds are fully efficacious at binding GR and causing the interaction with GRIP-1,a coactivator involved in repression of inflammatory genes by GR. The model suggests that this interaction is,in part,responsible for the anti-inflammatory activity of both compounds. Of course this is likely not the entire explanation. That said,when examining the ability of steroids and SGRMs to induce the interaction with PGC-1,a coactivator involved in glucose homeostasis in the liver among other things,a strikingly different result is found. The SGRM is weaker at inducing the PGC-1 interaction than the steroid. This may help explain the reduced negative impact on glucose metabolism from the SGRM. Thus,the reduced PGC-1 interaction may translate into reduced side-effects in liver and possibly other tissues as well.
J.N. Miner / Biochemical Pharmacology 64 (2002) 355±361 between GRIP and GR ef®ciently. This ®nding suggests exhibitactivitiesthathavethepromiseofleadingtopowerful, that the differences between AL-438 and steroids in vivo yet safer GR-dependent anti-in¯ammatory agents.
are not to be explained by the GRIP-1ÐGR interaction, with the caveat that we have not tested all cell contexts with this approach. Another example of potential coactivators for the GR is the PGC-1,originally characterized as a PPAR coactivator highly expressed in brown fat,involved [1] Rohatagi S,Rhodes GR,Chaikin P. Absolute oral versus inhaled in fat differentiation ,and more recently shown to play bioavailability: significance for inhaled drugs with special reference to inhaled glucocorticoids. J Clin Pharmacol 1999;39:661±3.
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Publikationsverzeichnis Prof. Dr. med. Anita Rauch A) Originalarbeiten 108. Göhring I, Tagariello A, Endele S, Stolt CC, Ghassibé M, Fisher M, Thiel CT, Trautmann U, Vikkula M, Winterpacht A, FitzPatrick DR, Rauch A (2009) Disruption of ST5 is associated with mental-retardation and multiple congenital anomalies. J Med Genet, in press 107. Segel R, Levy-Lahad E, Pasutto F, Picard


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