Recombinantly tailored reporter cell lines and 3D structure evaluations for improved drug development
The materials and know-how generated by our group largely facilitate and speed up drug development and target evaluation by high-thruput screening with target-oriented engineered reporter cell lines. This approach is applicable to a large number of pharmacological questions and will become of enormous importance with the increasing number of targets identified by genomics approaches. Recent conceptual and technical advancements in the molecular and structural biology of nuclear receptors provide exciting perspectives for pharmaceutical drug development. The possibilities of establishing highly specific cell-based in vivo screening systems for receptor ligands which act as agonists, antagonists or pure AP1 transrepressors and generating 3D structure information of the ligand binding domains will greatly improve the efficacy and quality of drug development, lowering costs and reduce animal experimentation. The aim of this project was to (i) develop technologies for the establishment and analysis of recombinantly tailored "reporter" cell lines and (ii) determine the structure of nuclear receptor ligand binding domains for the design and improvement of lead structures. Our aim was to pave the way towards the development of a new generation of high throughput screening systems in which the activity of a drug is monitored in the actual cellular target relative to non-target cells. We chose as model systems the nuclear receptor (steroid, thyroid, retinoid, vitamin D) and Ca++ signalling pathways. We wanted to generate stable cell lines in which a response is elicited by the NR ligand or Ca++ which can be easily monitored and quantified. Collectively, our study aimed at providing novel tools for pharmaceutical drug development and exploring the possibility of "tailoring" screening systems according to the drug target. Such systems are not only limited to nuclear receptors, but can be applied also to any target gene identified by a genomics approach.