Hydroxysteroid dehydrogenases: optimizing endogenous steroid hormone actions with SMD-inhibitor
Nuclear receptors: dissecting unexplored effects in an innovatiove manner
Multitarget NCEs: combining the evolving knowledge on steroid hormone biology

The introduction of transcriptional science as a enabling discipline for translational sciences will uncover innovative therapeutic avenues, most likely even for established or shelved compounds

Hormone action based therapies: unmeet success story in drug development for a plethora of diseases:

Exhaustive knowledge on the biological, cellular and medical functions of the natural steroid hormones and selective receptor ligands has accumulated since their discovery. These data provide a solid foundation for the identification of desired therapeutic effects; the challenge remains the site directed therapeutic exploitation of steroid hormone actions.

Hydroxysteroid Dehydrogenases allow therapeutic concepts that target desired effects in a tissue-specific manner. This may be of particular relevance for inflammatory diseases since cortisol metabolism has been demonstrated to be altered in rheumatoid arthritis. In fact, cortisol metabolism, the cortisol-cortisone-shuttle, had been proposed as a target for therapeutic intervention already in 1997 (Thomas Wilckens & Roel DeRijk, 1997); just recently Hardy et. al. demonstrated the validity of this concept by the identification of 11-beta-HSD in disease tissue of arthritis patients (Hardy et al. 2008).

Hydroxysteroid Dehydrogenases have been linked to a variety of diseases. The best described and validated indications for small molecule hydroxysteroid dehydrogenase-inhibitors target diabetes type 2, metabolic syndrome and other conditions associated with cortisol excess. Additional validated indications comprise breast and prostate cancer, as well as a variety of immune mediated disease, reproductive functions and aging related deficiencies. Steroid hormones are essentially and non-redundantly involved in almost all biological pathways; these comprise metabolic & reproductive functions, immunity and mechanisms like angiogenesis, apoptosis and annoikis. Therefore specific modulation of HSDs may allow the generation of highly innovative therapeutic concepts with small molecule HSD-inhibitors adressing major diseases with unmeet need..
Based on the ever increasing knowledge on the expression profiles and regulation of hydroxysteroid dehydrogeneases a plethora of new applications for hydroxysteroid dehydrogenase-inhibitors can be anticipated. Novel drug delivery technologies synergistically evolve and further widen the application potential for SMDs targeting SDRs or HSDs.

Combined with the emerging knowledge on downstream hormone actions, single target NCEs as well as multi-target compounds will allow the systematic exploitation of a plethora of underappreciated potential of steroid hormone biology.

Note that the slide below does not address the additional complexities arising from the interactions between GR and MR and cortisol acting on both receptors; compare slide under biological targets.

Adopted with kind permission from Rhen, T. and J. A. Cidlowski (2005). N. Engl. J. Med. 353: 1711.

Other references on HSDs, MR and GRand their newly emerging therapeutic potential as drug targets:

Zhang, J., et al. Characterization of a Novel Gain of Function Glucocorticoid Receptor Knock-in Mouse. J. Biol. Chem. 284, 6249-6259 (2009)
Chapman, K., et al. The role and regulation of 11beta-hydroxysteroid dehydrogenase type 1 in the inflammatory response. Mol Cell Endocrinol 301, 123-131 (2009)
De Bosscher, K. & Haegeman, G. Minireview: Latest Perspectives on Antiinflammatory Actions of Glucocorticoids. Mol. Endocrinol. 23, 281-291 (2009).
Margolis, R.N., Moore, D.D., Willson, T.M. & Guy, R.K. Chemical Approaches to Nuclear Receptors in Metabolism. Sci. Signal. 2, mr5- (2009).
Rickard, A.J. & Young, M.J. Corticosteroid receptors, macrophages and cardiovascular disease. J. Mol. Endocrinol. 42, 449-459 (2009).
Funder, J.W. Reconsidering the Roles of the Mineralocorticoid Receptor. Hypertension 53, 286-290 (2009).
Gross, K. & Cidlowski, J. Tissue-specific glucocorticoid action: a family affair. Trends Endocrinol Metab 19, 331-339 (2008).
Walker, B.R. Glucocorticoids and Cardiovascular Disease. Eur. J. Endocrinol. 157, 545-559 (2007).
Inhibition of 11-beta-hydroxysteroid dehydrogenase type 1 as a promising therapeutic target.
M Wamil and JR Seckl Drug Discov Today, Jul 2007; 12(13-14): 504-20.
Newton, R. & Holden, N.S. Separating Transrepression and Transactivation: A Distressing Divorce for the Glucocorticoid Receptor? Mol. Pharmacol. 72, 799-809 (2007).
AG Atanasov and A Odermatt Readjusting the glucocorticoid balance: an opportunity for modulators of 11beta-hydroxysteroid dehydrogenase type 1 activity? Endocr Metab Immune Disord Drug Targets, Jun 2007; 7(2): 125-40.
Wilckens, T. & De Rijk, R. Glucocorticoids and immune function: unknown dimensions and new frontiers. Immunol Today 18, 418-424 (1997)
Wilckens, T. Glucocorticoids and immune function: physiological relevance and pathogenic potential of hormonal dysfunction. Trends Pharmacol Sci 16, 193-197 (1995).

T Wilckens and A Volkmann 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. Arthritis Rheum, Jan 2007; 56(1): 387-8.

Days of Molecular Medicine: Inflammation in Chronic Disease May 24-27, 2006, Stockholm
Corticosteroid metabolism by 11beta-hydroxysteroid dehydrogenase:
  A novel drug target for rheumatoid arthritis Ariane Volkmann*, Tho Le#, Salvatore Albani# and Thomas Wilckens*
*BioNetWorks GmbH, Jakob-Klar-Str. 7, 80796 Munich, Germany  #UCSD, Department of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA

Arthritis_Hydroxysteroid_Dehydrogenase (Poster for download)

The poster presented at Days of Molecular Medicine: Inflammation in Chronic Disease May 24-27, 2006, Stockholm, shows BX-1, i.e. glycyrrhetinic acid, effects in several experimental settings. It should be noted, although others claim glycyrrhetinic acid completely halts bone loss in periodontal disease models ( bone loss related to periodontitis in Lewis rats was completely prevented), some of the experiments were not corroborated by other groups for unknown reasons. We reproduced in particular the early treatment regimens with different collaborating partners. Furthermore, glycyrrhetinic acid is a polypharmacologic and non-selective inhibitor of both 11-beta-HSD enzymes, thus the further validation of 11-beta-HSDs requires selective inhibitors. In summary, although we have a clear hypothesis how glycyrrhetinic acid affects disease progression in the models tested, there is currently no proof for any target or biological mechanism. Details will be discussed elsewhere or can be obtained from Dr. Thomas Wilckens: Thomas.Wilckens@InnVentis.com