Keynote and State-of-the-Art LEctures

This meeting features daily plenary lectures you won't want to miss. Select the links below to review the lecture summaries and register to attend today.

Monday, 26 June
Keynote Lecture: Ribosomes as Targets for New Antibacterials

Daniel N. Wilson, University of Hamburg

The ribosome is one of the main antibiotic targets in the bacterial cell. Structures of naturally produced antibiotics and their semi-synthetic derivatives bound to ribosomal particles have provided unparalleled insight into their mechanisms of action, and they are also facilitating the design of more effective antibiotics for targeting multidrug-resistant bacteria. In this presentation, I will discuss the recent structural insights into the mechanism of action of ribosome-targeting antibiotics and the molecular mechanisms of bacterial resistance, in addition to the approaches that are being pursued for the production of improved drugs that inhibit bacterial protein synthesis. 

References:

  1. Arenz S, Wilson DN. (2016) Blast from the Past: Reassessing Forgotten Translation Inhibitors, Antibiotic Selectivity, and Resistance Mechanisms to Aid Drug Development. Mol Cell. 61(1):3-14. 
  2. Wilson DN. (2014) Ribosome-targeting antibiotics and mechanisms of bacterial resistance. Nat Rev Microbiol. 2014, 12(1):35-48.
  3. Sohmen D, Harms JM, Schlunzen F, Wilson DN (2009) SnapShot: Antibiotic inhibition of protein synthesis I. Cell 138: 1248 e1241.

Tuesday, 27 June
State-of-the-Art Lecture 1: Undruggable Targets

Peter Wipf, University of Pittsburgh

Druggability refers to the property of a biological pathway or molecule, mainly a protein, to serve as a target for a small molecule therapeutic of a human disease. Currently, only about 2% of the proteins encoded by the ca. 20,000 genes in the human genome are targeted by approved small molecule drugs. Even if ultimately only 10-15% of proteins prove to be disease-modifying, this means that after many decades of rational drug discovery, many cellular components and mechanisms of action remain therapeutically orphaned. Efforts to develop this large pool of potential targets have faced a multitude of obstacles. These include a focus on potent active-site protein ligands that disrupt catalytic processing, and a conservative industry approach that relies on validation and clinical precedence prior to investing significant development funds. Additional obstacles are the preponderance of protein-protein interactions (PPIs) in the functional control of many cellular signaling pathways and networks, and the lack of classical deep binding pockets in some protein families, such as transcription factors and phosphatases, which often feature flat hydrophobic surface areas. Last, but not least, there is a reluctance in the field to engage classes of compounds that are traditionally considered as non drug-like, such as carbohydrates and lipids, which nonetheless often serve as critical protein modifications and intra- and extracellular sensors and messengers.

This presentation will focus on three specific “undruggable targets”, with the implication that while currently still “undrugged” these targets are within the reach of novel strategies aimed at expanding the utility of new therapeutics. For example, the protein phosphatase PTP4A3 is an attractive anticancer target, but knowledge of its exact role in cells remains incomplete. Selective intracellular regulation of phosphatases with small molecule inhibitors has been an unmet general challenge. Similarly, protein homeostasis is a critical process in stress, disease and aging, and dysregulation can affect cancer, neurodegenerative and inflammatory diseases. For this purpose, we have been developing modulators of the heat-shock protein Hsp70 and the AAA ATPase p97. Finally, reactive oxygen species (ROS) can trigger apoptotic and ferroptotic cell death, but ROS also have important roles in cell signaling. To circumvent the limitations of natural antioxidants, we have been developing mitochondrial-targeted ROS scavengers that prevent cardiolipin (CL) oxidation and augment CL-dependent cell survival pathways.

Lead references: (a) Salamoun, J. M.; Wipf, P., Allosteric modulation of phosphatase activity may redefine therapeutic value. J. Med. Chem. 2016, 59, 7771; (b) Posimo, J. M. et al., Heat shock protein defenses in the neocortex and allocortex of the telencephalon. Neurobiol. Aging 2015, 36, 1924; (c) Alverez, C. et al., Structure-activity study of bioisosteric trifluoromethyl and pentafluorosulfanyl indole inhibitors of the AAA ATPase p97. ACS Med. Chem. Lett. 2015, 6, 1225; (d) Krainz, T. et al., A mitochondrial-targeted nitroxide is a potent inhibitor of ferroptosis. ACS Centr. Sci. 2016, 2, 653.


Wednesday, 28 June
State-of-the-Art Lecture 2: CYP2D6: A Paradigm for Understanding Genetic Variability in DMPK

Andrea Gaedigk, Children's Mercy Kansas City

CYP2D6 is one of the most extensively studied drug metabolizing enzymes owing to its contribution to the metabolism of about 25% of clinically used drugs including antidepressants, antipsychotics, opioids and the selective estrogen receptor modulator tamoxifen. It’s highly polymorphic nature leads to a wide range of activity among individuals within a given population and among world populations. Genetic variation has been shown to be the single most important factor explaining variability in drug metabolism. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has now published four clinical practice guidelines for drugs metabolized by CYP2D6 (codeine, tricyclic antidepressants, SSRIs and ondansetron) facilitating the translation of genotype test results into actionable prescribing decisions. One of the major challenges of implementing precision therapeutics is, however, to also understand other factors such as obesity that may influence the response to a particular drug at the level of the individual patient. The implementation of precision medicine poses even greater challenges for the pediatric patient as ontogeny (growth and development) can impact metabolic pathways involving drug absorption, distribution, metabolism and excretion. Clearly, children are not just ‘small’ adults. The GOLDILOKs (Genomic- and Ontogeny-Linked Dose Individualization and cLinical Optimization for Kids) Initiative at Children’s Mercy in Kansas City aims to address existing knowledge deficits and bring precision therapeutics -- the dose of medication that is “not too big, not too small … but just right” -- to children of all ages. To address a number of barriers and knowledge gaps we are pursuing a response -> exposure -> dose paradigm as an alternative to the traditional dose -> exposure -> response approach to directly target variability in drug response. To that end, we are using atomoxetine as the proof-of-concept experimental paradigm. Atomoxetine is a norepinephrine (noradrenaline) reuptake inhibitor approved for the treatment of attention-deficit/hyperactivity disorder in children, adolescents and adults. For this drug, a wide range of variability in drug exposure presents a major confounding factor to clinical response. The development and validation of population PK (popPK) and physiology-based PK (PBPK) models to control the dose -> exposure relationship will provide invaluable information to minimize variability in drug exposure at the level of the individual patient. We are also further improving CYP2D6 phenotype prediction from genotype data by utilizing Next-Generation Sequencing and a bioinformatic tool, Astrolabe, to call genotype from NGS data. Phenotype information using a refined Activity Score system will be incorporated into the popPK and PBPK models. Lastly, we are utilizing our pediatric liver bank to build “bottom-up” PBPK models to individualize dosing in children, especially when existing pediatric knowledge is limited or non-existent. Although our efforts are focused on the pediatric population and genes impacting atomoxetine metabolism and drug response, our approach can be adapted to other drugs and/or populations of interest.


Thursday, 29 June
State-of-the-Art Lecture 3: The Promises and Challenges of Cancer Epigenetics

Daniel Neureiter, Paracelsus University

Our scientific knowledge on the role of epigenetic regulation via DNA methylation, histone acetylation, as well as by microRNAs (miRNAs) in humans has essentially increased in the last years (e.g. Chromosoma. 2016;125(1):75-93). Coming from epigenetic insights in processes of development and embryology, the scientific focus of epigenetics is currently translated to human carcinogenesis and its role in cancer initiation, progression and metastasis. Here, we have already gained deep information on many genes which are targets of DNA methylation, histone acetylation and miRNAs and are central to the hallmarks of cancer, whereby data on possible mechanistic cooperations and regulations of each other in a specific pathological context are missing or rather incomplete until now. Consecutively, the development of epigenetic activators and inhibitors were successfully initiated in experimental settings. These epigenetic modulators (pharmacological activators and inhibitors) target DNA methyltransferases and histone (de-)acetyltransferases and (de-)methyltransferases as well as distinct sets of chromatin readers. Most of these developed epigenetics-modulating substances showed significant and specific anti-cancer effects (anti-proliferative or pro-apoptotic), whereby “alternative” cancer-related processes (such as endoplasmatic stress or autophagy) are also be addressed by these epigenetic drugs demonstrating their enormous potency for application in clinical application.
Interestingly, the transfer of these drugs to clinical setting is rather sobering: only a minority of epigenetic drugs have currently been approved by the FDA (Food and Drug Administration) such as decitabine and azacitidine for MDS, vorinostat and romidepsin for cutaneous T-cell lymphoma (TCL) as well as recently panobinostat and belinostat for the treatment of multiple myeloma and peripheral TCL (Database (Oxford). 2016 Dec 26;2016).

Additionally, detailed in-vitro and in-vivo as well in-situ-analysis revealed structured information of methylation and acetylation as well as miRNA status in heterogeneous malignancies referred to the terms of “Methylome”, “Acetylome” and “miRNome”. These findings could lead (i) to the development of new highly selective epigenetic drugs on the one hand and, (ii) to personalized and precise selection of patients according to their their cancer’s epigenetic profiling on the other hand. Own experience could demonstrate, that HDAC expression showed highly different patterning in the same tumor entity highlighting the need for systematical and cancer-entity-related epigenetic investigations.

Another two very interesting approaches in the field of cancer epigenetics are associated with the interaction between themselves and their additive or synergistic effects with other “classical” or “biological” drugs. Own in-silico-analysis revealed that the crosstalk of histone acetylation and miRNAs in human carcinogenesis and chronic diseases is linked to specific pathways like the a-(1,6)-fucosyltransferase, polycystin-2 and the fibroblast- growth-factor 2 pathways (Expert Opin Biol Ther. 2015 May;15(5):651-64). Furthermore, an increasingly important field of interest will be the interaction of epigenetics with standard drugs by (i) inducing re-expression of oncogenetically altered proteins for targeting or, (ii) by preventing the development of drug resistance.

Nowadays, different high-throughput and affordable molecular platforms dealing with epigenetic profiling (Mol Cell. 2015;58(4):586-97) have become available to investigate the epigenetic status in high performance and in time which will fundamentally change our therapeutic repertoire in future (Recent Pat Anticancer Drug Discov. 2016;11(4):424-433.).