REVIEWS Drug Discovery Today  Volume 12, Numbers 19/20  October 2007 Panning for SNuRMs: using cofactor profiling for the rational discovery of selective nuclear receptor modulators Claus Kremoser 1 , Michael Albers 1 , Thomas P. Burris 2 , Ulrich Deuschle 1 and Manfred Koegl 3 1 Phenex Pharmaceuticals AG, Gebaeude J542N, Werksgelaende BASF, D-67056 Ludwigshafen, Germany 2 Nuclear Receptor Biology Laboratory, Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70808, USA 3 Translational Research, Genomics and Proteomics Core Facility, German Cancer Research Center DKFZ, Im Neuenheimer Feld 515, D-69120 Heidelberg, Germany Drugs that target nuclear receptors are clinically, as well as commercially, successful. Their widespread use, however, is limited by an inherent propensity of nuclear receptors to trigger beneficial, as well as adverse, pharmacological effects upon drug activation. Hence, selective drugs that display reduced adverse effects, such as the selective estrogen receptor modulator (SERM) Raloxifene, have been developed by guidance through classical cell culture assays and animal trials. Full agonist and selective modulator nuclear receptor drugs, in general, differ by their ability to recruit certain cofactors to the receptor protein. Hence, systematic cofactor profiling is advancing into an approach for the rationally guided identification of selective NR modulators (SNuRMs) with improved therapeutic ratio. Introduction Nuclear receptors (NRs) are a family of transcription factors that constitute an important and successful class of drug targets (reviewed in references [1–3]). Many of them are regulated by the binding of low-molecular weight ligands, such as steroid hormones or cholesterol metabolites, and for all nuclear receptors where a natural ligand is known, synthetic compounds that mod- ulate the receptor’s activity have been identified. However, the pleiotropic effects of NR activity make NR-based drugs, in general, sharp but double-edged swords. Examples of NR targets whose drugs typically exhibit adverse effects that limit their use are the glucocorticoid (NR3C1) and the estrogen (NR3A1, NR3A2) nuclear receptors. The potent anti-inflammatory activity of glucocorti- coids is limited to severe applications because of side effects such as Cushing Syndrome, hyperglycaemia and bone loss [4]. Post- menopausal hormone replacement therapy with natural estrogens that target the estrogen receptors (ERs) is limited by their prolif- erative activity in breast and endometrial tissue, leading to increased risk for reproductive cancers. Current efforts, therefore, aim to develop drugs that modulate nuclear receptors in a tissue and/or gene-specific way. The first hint that this was possible came from selective estrogen receptor modulators (SERMs) such as raloxifene, which, unlike other SERMs and natural ER ligands, do not cause the problematic endometrial activation of ER [5,6]. This example of tissue-selective activation of an NR has instigated the quest for selective nuclear receptor modulators. How are nuclear receptors activated to yield a transcriptional response? To understand how SNuRMs might work, one needs to consider how nuclear receptors exert their function on a molecular level. The general layout of the nuclear receptor protein family is con- served: An N-terminal domain, which varies widely amongst family members, is followed by the well-conserved DNA binding domain (DBD), which uses two highly conserved zinc fingers to recognise NR-response DNA elements [7,8]. A less well-conserved hinge region connects the DBD to the ligand-binding domain (LBD), a globular alpha-helical three-layered ‘sandwich’ that har- bours the cavity for the natural or synthetic ligand [9–12] reviewed in reference [13]. Activation of transcription involves modification of chromatin proteins, alterations in chromatin structure and recruitment of the transcriptional machinery. NRs drive chromatin modifications by serving as ‘landing platforms’ for numerous proteins or protein Reviews  POST SCREEN Corresponding author: Kremoser, C. (claus.kremoser@phenex-pharma.com) 860 www.drugdiscoverytoday.com 1359-6446/06/$ - see front matter ß 2007 Published by Elsevier Ltd. doi:10.1016/j.drudis.2007.07.025