The 8th International Summer School “Medicinal Chemistry”, organized by the DFG Research Training Group GRK1910 “Medicinal Chemistry of Selective GPCR Ligands”, took place at the University of Regensburg, September 21 – 23, 2016. Sixteen distinguished scientists from academia and industry accepted the invitation to contribute to a program combining teaching and cutting-edge research.
The opening lecture on antiinflammatory drugs was held by Prof. Peter Bernstein (University of Delaware), who gave a comprehensive overview on recent developments and trends in this field, ranging from approaches to the modulation of the arachidonic acid pathway to novel promising therapeutic concepts targeting various key molecules in “inflammasome activation” and signaling. For example, the downregulation of inflammatory cytokines such as TNFα, IFN-γ, IL-2 and IL-10 by catechol or boronic acid based PDE4 inhibitors was discussed. The ceramide pathway with sphingosine-1-phosphate modulators as well as members of the kinase family were presented as further candidates harbouring a potential for novel antiinflammatory drugs.
Specific kinases as potential drug targets for the treatment of chronic diseases were the topic of Prof. Stefan Laufer’s (University of Tübingen, Germany) talk. He reported on the development of a novel series of immunomodulatory tricyclic JAK inhibitors with selectivity for JAK3 over other members of the JAK family.
In the session on structural biology and drug discovery, the increasing contribution of protein crystallography was substantiated by Dr. Alexander Pautsch (Boehringer Ingelheim Pharma, Germany), who presented different case studies considering crystal structures of kinases (e. g. CDK1, PI3-Kinase γ) and hepatitis C virus NS5B polymerase and the discovery and optimization of inhibitors.
Dr. Michael Henning (leadXpro, Switzerland) gave an overview on serial crystallography, X-ray FEL (free electron laser) and single particle electron microscopy and the impact of these technologies on structure-based drug discovery in the case of membrane proteins such as GPCRs, ion channels and transporters.
In the session on GPCRs and GPCR ligands Prof. Holger Stark (University of Düsseldorf, Germany) reported on histamine H3 receptor antagonists and the design of hybrid drugs addressing multiple targets that are of relevance for the same disease. An expert overview was given on the potential of H3 receptor antagonists for the treatment of CNS diseases such as M. Parkinson, M. Alzheimer or schizophrenia.
Professor Beili Wu (Shanghai Institute of Materia Medica, China) provided detailed insight into the recently crystallized human purinergic P2Y1 receptor in complex with a nucleotide (MRS2500) and a non-nucleotide (BPTU) antagonist. The two ligands bind at different sites: MRS2500 recognizes a site within the seven transmembrane bundle, but distinct from the nucleotide site, whereas BPTU occupies an allosteric pocket on the external receptor interface with the lipid bilayer. This makes BPTU the first structurally characterized GPCR ligand located entirely outside the transmembrane bundle. Prof. Wu’s stay at the University of Regensburg was supported by the Regensburger Universitätsstiftung Hans Vielberth.
Prof. Annette Beck-Sickinger (University of Leipzig, Germany) discussed recent advances in the field of peptides targeting GPCRs. She analyzed the roles that peptides currently play in medicinal chemistry and their use not only as biologically active ligands, but also as selective carriers for the delivery of therapeutic agents, and presented novel results from her laboratory on neuropeptide Y receptors and their peptidic ligands.
Prof. Patrick Vanderheyden (Vrije Universiteit Bruessel, Belgium) emphasized the relevance of residence time in receptor-ligand studies, which is a hot topic in drug research. Slow dissociation rates of ligands may suggest insurmountable antagonism. Long receptor residence time represents a key factor in the efficiency and duration of action of drugs, as exemplified by Prof. Vanderheyden for a series of AT1 receptor antagonists.
The optimization of drugs and agrochemicals was the topic of the fourth session. Dr. Hans Matter (Sanofi-Aventis, Frankfurt, Germany) gave an overview about models of multidimensional compound optimization, combining target activity and ADMET (absorption, distribution, metabolism, excretion, toxicity) properties at very early stages of drug discovery (substantiated by examples) to reduce cycle times and to increase productivity and efficiency.
Dr. Wilhelm Amberg (AbbVie Deutschland, Ludwigshafen, Germany) presented an overview on the development of CNS drugs with focus on the ability of compounds to cross the blood brain barrier. He explained different models for the prediction and optimization of CNS penetration by balancing of physicochemical properties addressed pitfalls and limitations, for example, in case of substrates of transporters expressed in the blood-brain barrier resulting in poor brain access of the respective compounds.
Dr. Ralph Lipp (Lipp Life Science, Indianapolis, USA) focused his talk on strategies aiming at reducing the impact of attrition in discovery and early drug development. He presented case studies taking into consideration the reduction of costs in different phases as well as the major attrition drivers, in particular, inadequate pharmacokinetics and/or efficacy. Special attention was paid to attempts (exemplified by case studies with positive and negative outcome) to predict the program risk based on, e.g., the drug-like space, the physicochemical properties, preclinical data, and PK/PD modeling. In view of pipeline drugs, there is a trend towards low solubility, which often translates in poor exposure. Therefore, technological approaches such as sophisticated formulations harbor a high potential with regard to reducing the attrition rate.
Dr. Clemens Lamberth (Syngenta Crop Protection AG, Stein, Switzerland) reported on scaffold hopping approaches in the optimization of agrochemicals. The discovery and development of agrochemicals shows several analogies with drug research, for example, with respect to chemistry- and target-driven approaches, inspiration by natural products, computational modeling, combinatorial chemistry, optimization of physicochemical properties, considering (eco)toxicological aspects. However, the launch of agrochemicals is substantially faster than that of drugs. The incorporation of “exotic” substructures into agrochemicals represents an efficient strategy to overcome patents.
The last session, dealing with cancer diagnostics and therapeutics, was opened by Prof. Dirk Hellwig (University Hospital Regensburg, Germany). He reviewed state-of-the-art radioactive receptor ligands in diagnostic (molecular imaging) and therapeutic nuclear medicine (theragnostics). For example, 177Lu-labeled somatostatin analogs were efficient in the treatment of neuroendocrine tumors. In addition, he presented very recent promising results that were achieved in the diagnostics and therapeutics of prostate cancer with PSMA-based theragnostics using 68Ga-, 177Lu- and 255Ac-labeled radiopharmaceuticals.
Prof. Olaf Prante (Universitätsklinikum Erlangen, Germany) presented an overview on different 18F-fluoroglycosylation reactions that were devised for the preparation of receptor ligands as tracers for positron emission tomography (PET). A broad application of PET became possible with the convenient synthesis of [18F]fluorodesoxyglucose. Meanwhile, various strategies for chemoselective 18F-labeling have been explored to obtain PET tracer with a favorable biodistribution. Olaf Prante presented attractive versatile 18F-fluoroglycosylation techniques, e. g., coupling to GPCR ligands via copper-catalyzed azide-alkyne cycloaddition.
Dr. Kurt Ritter (Sanofi-Aventis, Frankfurt, Germany) gave an introduction into current approaches to the immunotherapy of cancer. Antibodies against immune checkpoints (e.g. CTLA-4, PD-1, PDL-1) are of special interest to (re)activate the immune system to attack cancer cells. At present, antibodies addressing such checkpoints are considered very promising, especially, when combined with other anticancer agents. Other approaches aiming at restoring T-cell activity are, e.g., the development of inhibitors of indoleamine-2,3-dioxygenase 1 (IDO1), TRP-2,3-dioxygenase (TDO), the application of anti-CD73 antibodies or A2A receptor antagonists.
Finally, Dr. Timo Stellfeld (Bayer Healthcare, Berlin, Germany) reported on the discovery and characterization of the first inhibitor of the lysine methyltransferase SMYD2 enabling target validation in rodents. Although it is accepted that SMYD2 plays a role in promoting cancer, its physiological and pathophysiological relevance is far from being understood, as the enzyme does not exclusively methylate histone proteins. The highly potent and selective aminopyrazoline-based inhibitor BAY-598 turned out to be a very useful pharmacological tool to study SMYD2.
The participants, PhD students and postdoctoral researchers, presented their scientific results on posters and in short oral communications and had the opportunity to discuss their work with the invited speakers as well as with peers. Five posters were awarded a prize.
Taken together, the combination of lectures covering teaching of state-of-the-art technologies, concepts in drug discovery and development, the presentation of case studies and cutting-edge research by experts and key players as well as the international networking opportunities were highly appreciated by the audience.