Rational discovery of novel nuclear hormone receptor antagonists

Nuclear hormone receptors (NRs) are potential targets for therapeutic approaches to many clinical conditions, including cancer, diabetes, and neurological diseases. The crystal structure of the ligand binding domain of agonist-bound NRs enables the design of compounds with agonist activity. However, with the exception of the human estrogen receptor-alpha, the lack of antagonist-bound "inactive" receptor structures hinders the rational design of receptor antagonists. In this study, we present a strategy for designing such antagonists. We constructed a model of the inactive conformation of human retinoic acid receptor-alpha by using information derived from antagonist-bound estrogen receptor-alpha and applied a computer-based virtual screening algorithm to identify retinoic acid receptor antagonists. Thus, the currently available crystal structures of NRs may be used for the rational design of antagonists, which could lead to the development of novel drugs for a variety of diseases.

[1]  M. Gottardis,et al.  Beyond tamoxifen: the retinoid X receptor-selective ligand LGD1069 (TARGRETIN) causes complete regression of mammary carcinoma. , 1998, Cancer research.

[2]  H. Gronemeyer,et al.  The nuclear receptor ligand-binding domain: structure and function. , 1998, Current opinion in cell biology.

[3]  L. Hamann,et al.  Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists , 1997, Nature.

[4]  E C Dees,et al.  Recent advances in systemic therapy for breast cancer , 1998, Current opinion in oncology.

[5]  R. Heyman,et al.  Retinoic Acid Receptor α Expression Correlates with Retinoid-induced Growth Inhibition of Human Breast Cancer Cells Regardless of Estrogen Receptor Status , 1997 .

[6]  B J Hoffer,et al.  Dopamine neuron agenesis in Nurr1-deficient mice. , 1997, Science.

[7]  R. Chandraratna,et al.  Identification of a retinoic acid receptor alpha subtype specific agonist. , 1996, Journal of medicinal chemistry.

[8]  A. Fanjul,et al.  Apoptosis induction and potent antiestrogen receptor-negative breast cancer activity in vivo by a retinoid antagonist. , 1998, Cancer research.

[9]  H P Koeffler,et al.  Effects of novel RAR- and RXR-selective retinoids on myeloid leukemic proliferation and differentiation in vitro. , 1999, Blood.

[10]  William Bourguet,et al.  Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-α , 1995, Nature.

[11]  E. Baulieu,et al.  RU486 (mifepristone): mechanisms of action and clinical uses. , 1997, Annual review of medicine.

[12]  Fernand Labrie,et al.  EM-800, a Novel Antiestrogen, Acts as a Pure Antagonist of the Transcriptional Functions of Estrogen Receptors α and β. , 1998, Endocrinology.

[13]  P. Sigler,et al.  Atomic structure of progesterone complexed with its receptor , 1998, Nature.

[14]  R. Chandraratna,et al.  Future trends: a new generation of retinoids. , 1998, Journal of the American Academy of Dermatology.

[15]  Lucia Riccardi,et al.  RARα antagonist RO 41‐5253 inhibits proliferation and induces apoptosis in breast‐cancer cell lines , 1998 .

[16]  J. Cherfils,et al.  Molecular docking programs successfully predict the binding of a β-lactamase inhibitory protein to TEM-1 β-lactamase , 1996, Nature Structural Biology.

[17]  R. Abagyan,et al.  Biased probability Monte Carlo conformational searches and electrostatic calculations for peptides and proteins. , 1994, Journal of molecular biology.

[18]  P. Chambon,et al.  Conformational adaptation of agonists to the human nuclear receptor RARγ , 1998, Nature Structural Biology.

[19]  William Bourguet,et al.  A canonical structure for the ligand-binding domain of nuclear receptors , 1996, Nature Structural Biology.

[20]  B. Spiegelman.  PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. , 1998, Diabetes.

[21]  B M Raaka,et al.  The ligand-binding domains of the thyroid hormone/retinoid receptor gene subfamily function in vivo to mediate heterodimerization, gene silencing, and transactivation , 1995, Molecular and cellular biology.

[22]  R. Lotan,et al.  Differential effects of synthetic nuclear retinoid receptor-selective retinoids on the growth of human non-small cell lung carcinoma cells. , 1997, Cancer research.

[23]  Zbigniew Dauter,et al.  Molecular basis of agonism and antagonism in the oestrogen receptor , 1997, Nature.

[24]  Jean-Paul Renaud,et al.  Crystal structure of the RAR-γ ligand-binding domain bound to all-trans retinoic acid , 1995, Nature.

[25]  Ruben Abagyan,et al.  NRIF3 Is a Novel Coactivator Mediating Functional Specificity of Nuclear Hormone Receptors , 1999, Molecular and Cellular Biology.

[26]  David A. Agard,et al.  The Structural Basis of Estrogen Receptor/Coactivator Recognition and the Antagonism of This Interaction by Tamoxifen , 1998, Cell.

[27]  C. Thiele,et al.  Activation of Three Distinct RXR/RAR Heterodimers Induces Growth Arrest and Differentiation of Neuroblastoma Cells* , 1997, The Journal of Biological Chemistry.

[28]  Elazer R. Edelman,et al.  Adv. Drug Delivery Rev. , 1997 .

[29]  H P Koeffler,et al.  Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Ruben Abagyan,et al.  Detailed ab initio prediction of lysozyme–antibody complex with 1.6 Å accuracy , 1994, Nature Structural Biology.

[31]  H Grøn,et al.  Estrogen receptor (ER) modulators each induce distinct conformational changes in ER alpha and ER beta. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[32]  T. Willson,et al.  Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ , 1998, Nature.