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Principle Investigators: Heiko Funke-Kaiser, Ulrike Muscha Steckelings, Franz Theuring, Thomas Unger, Ulrich Kintscher
Partners: Prof. Jürgen Scholze , Charité Campus Mitte, Berlin, Klinik für Innere Medizin/ Kardiologie am Deutschen Herzzentrum Berlin
Drug development is a complex, time- and cost-intensive process involving different disciplines from medicine and natural sciences. Classically, drug development can be divided into two sequential modules called drug discovery and drug development (subsequent figure). Discovery comprises all steps from the therapeutic concept, i.e. from the biological target, to the molecule, whereas development encompasses the operating processes from the molecule to the registered drug. Discovery often starts with target identification, e.g. the cloning and (patho)physiological characterisation of a novel gene. A crucial step in early drug discovery is assay development. This can be accomplished through the generation of stable cell lines and a luciferase-based read-out to measure receptor activity. A high-throughput screening (HTS; primary screening) to explore the chemical space for pharmacological activities represents the next step which can be performed in cooperation with contract research organisations (CROs). So-called confirmed compounds resulting from the HTS are validated by a secondary screening to yield hits. The hit-to-lead programme addresses aspects such as structure-activity-relationships (SAR)/ definition of a pharmacophore, determination of affinity (KD) and potency (IC50), specificity/ selectivity (panel-screens), pharmacokinetic (i.e., absorption, distribution, metabolism, excretion (ADME)) and toxicological (T) parameters. The hit-to-lead programme can be viewed as a filtering process to narrow down the hundreds and thousands of hits generated by the HTS/ secondary screening, but also comprises synthetic chemistry (medicinal chemistry (MC)) steps. Leads - chemical structures with a potency in the 1-10 microM range, selectivity and appropriate ADMET parameters - represent the milestone of the hit-to-lead programme.
The lead-to-candidate programme, also named lead optimisation phase, aims to further increase affinity/ potency, specificity/ selectivity and ADMET properties by using e.g. in vivo ADMET analyses. The in vivo proof-of-concept (PoC) is a crucial milestone within the lead-to-candidate programme to analyse if a certain compound is effective with respect to a certain indication in an animal model. So-called developmental candidates have passed the PoC and are further optimised by MC to attain e.g. a potency in the 1-10 nM range, which is a usual prerequisite for clinical candidates for the first trials in humans.
The clinical phase of drug development comprises for defined phases: Phase I studies are performed on a small group of healthy volunteers with the aim to check for drug safety, tolerability, and pharmacokinetic properties. Phase II studies are performed on groups of patients with a defined set of indications to test for clinical efficacy, and for dose finding analysis. Often such studies will cover several distinct clinical disorders to identify the possible therapeutic indications for the new compound. Phase III trials are the definitive double-blind randomised trials, commonly performed as multicentre trials on 1000-3000 patients, aimed at comparing the new drug with commonly used alternatives. At the end of a "successful" phase III, the drug will be submitted to the relevant regulatory authority for licensing. Phase IV studies comprise the obligatory postmarketing surveillance designed to detect any long-term adverse effects. More importantly, these studies are important to identify new potential indications for the drug in a clinical setting in many thousands of patients.
Clinical studies are a major cornerstone of the drug development agenda and the translational research approach at the CCR. In close collaborations with clinical departments, in particular the Outpatient Department at the Charité Campus Mitte under the guidance of Prof. Jürgen Scholze, and the Department of Internal Medicine/ Cardiology at the German Heart Institute, multiple clinical trials are currently conducted in different clinical phases and cardiovascular indications. In addition, clinical investigators with a focus on cardiovascular research from various departments at the Charité have their laboratories at the CCR, and provide an optimal platform for mutual research interactions.
|Drug discovery & drug development||Principle Investigators|
|target identification and validation||Funke-Kaiser/Unger, Kintscher|
|assay development to hit-to-lead-programme||Funke-Kaiser/Unger, Kintscher|
|lead-to-candidate-programme, e.g./ preclinical in vivo prrof-of-concept/in vivo evaluation of different indications||Steckelings/Unger, Hocher, Theuring|
To give an example, Prof. Dr Thomas Unger and Dr. Ulrike Steckelings are in strategic partnership with the company Vicore Pharma to contribute to the preclinical and clinical development of AT2 Receptor Agonists.
Moreover two drug developing companies were founded by members of the CCR as spin offs of the Charité. CCR Pharma was founded by PD Dr. Heiko Funke-Kaiser, Prof. Dr. Thomas Unger, Frank Zollmann and Dr. Jan Schefe and is developing prorenin/ rennin receptor (RER) antagonists as potential future cardiovascular drugs, a project funded by the "Go Bio" program of the BMBF (http://www.ccr-pharma.de)
The company of Prof. Dr. Franz Theuring is targeting neurodegenerative diseases (TauRx Pharmaceuticals).
For more detailed information on the various projects please refer to the chapters of the individual research groups.