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Title:Computational and synthetic approaches in the design and development of chemical probes for estrogen receptor function
Author(s):Mayne, Christopher G.
Director of Research:Katzenellenbogen, John A.
Doctoral Committee Chair(s):Katzenellenbogen, John A.
Doctoral Committee Member(s):Hergenrother, Paul J.; Nardulli, Ann M.; Burke, Martin D.
Department / Program:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Estrogen Receptor
Progesterone Receptor
Abstract:A member of the nuclear receptor superfamily, the estrogen receptor (ER) is a ligand-regulated transcription factor responsible for the regulation of hundreds of genes. Consequently, ERs are involved in numerous disease states, including cellular proliferation, post-menopausal symptoms, inflammation, and neurodegeneration, all of which represent potential opportunities for endocrine therapies. Sustained efforts in structural biology have led to the deposition of many high resolution x-ray crystal structures of ligand-receptor complexes into the PDB, and provide valuable insight into the key ligand-receptor interactions determining binding affinity and, in some cases, specific macroscopic structural attributes that directly affect ER function. As described herein, we have leveraged selected PDB structures, supplemented by additional unpublished structures obtained from collaborators, to design and develop chemical probes of ER function. The underlying mechanisms driving ligand affinity and selectivity remain a key focus in understanding ER function. Correspondingly, we describe the development of imidazo[1,2-a]pyridine ligands to probe the importance of the core scaffold structure in ligand binding affinity. Computational analysis of ligand and receptor structures has led to the identification of the interaction between their respective dipole moments as an important receptor-ligand interaction. We also set out to discover novel ER scaffolds through a virtual screening approach and follow-up synthetic efforts to identify and further investigate a thiadiazole scaffold bearing an extended alkyl substituent. Docking structures suggest an intriguing binding mode probing the presence of a putative second binding volume reminiscent of that observed for the high affinity and highly selective glucocorticoid receptor (GR) ligand, deacylcortivazol (DAC). The diverse biological roles of ERs also provide opportunities to probe receptor function through alternative mechanisms. We report the use of recent crystal structures to design novel modifications of known ER ligands in probing the molecular basis for receptor crosstalk between ER and NF-κB, and the resulting effect on inflammatory pathways. These ligand modifications are centered on destabilizing helix 12 by disrupting the position of a single histidine residue within the binding pocket, and have been shown to effect antagonist activity on both classical ER pathways and the expression of IL-6, the latter being representative of inflammatory responses, in vivo. Previous work in our labs has also demonstrated that the assessment of ER-dependent targets can provide a better indication of ER function in vivo than assaying ER itself. To this end, we have developed new scoring functions for evaluating docked structures of fluorinated analogues of Tanaproget for the progesterone receptor (PR), whose expression is tightly controlled by ER. These functions have been applied in the design and selection of new synthetic targets for use in imaging ER-positive tumors via positron emission tomography (PET).
Issue Date:2011-05-25
Rights Information:Copyright 2011 Christopher G. Mayne
Date Available in IDEALS:2011-05-25
Date Deposited:2011-05

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