Author: Katja Herzog

Felix Hausch is professor for structure-based drug research at the Technical University Darmstadt. He is a recognized expert for the chemical biology of immunophilins (mainly FKBPs) and has discovered the SAFit class of selective FKBP51 ligands. He has authored 82 publications (incl. Nat Chem Biol, Angew Chem, JACS; h-factor= 34 (Google Scholar)) and >10 accepted patent families. He is speaker of the LOEWE consortium TRABITA, Core team member of the Zukunftscluster PROXIDRUGS, coordinator of the BMBF consortia iMIP and 51TaValP, co-coordinator of the VIP+ consortium Fit4Fat and of the ANR/BMBF consortium SIAM. Felix Hausch received his PhD from the Free University Berlin in 2000, gained postdoc experience at Stanford University and biotech industry in Zurich (ESBATech AG, 2 years), and was group leader at the Max-Planck Institute of Psychiatry and lecturer at the LMU (Munich, 2005-2016).

Abstract:

De novo identification of a fully synthetic FKBP12-FRB Molecular Glue

Topic:

The gain-of-function pharmacology of Molecular Glues, prominently exemplified by the immunosuppressants FK506 and Rapamycin, holds great potential to address otherwise intractable targets. So far, the known Molecular Glues have been largely discovered by serendipity or in a target-agnostic manner. To explore the probability for the existence of Molecular Glues, we performed a targeted screen for Molecular Glues for FKBP12-FRB( FKBP-Rapamycin binding domain of mTOR), using Rapamcin as an established control. From our in-house FKBP-targeted ligand library, we identified a weak hit, that was validated in an FP-based secondary assay. Surprisingly, the structure of the ternary complex revealed a new binding mode of this hit compared to Rapamycin, which allow chemical optimization resulting in a fully synthetic FBKP12-FRB Molecular Glue with sub-micromolar efficacy. Our results show that with a focused library and a tailored assay cascade a targeted de-novo screening for Molecular Glues is feasible.

Alberto Dal Corso studied chemistry at Università degli Studi di Milano, where he obtained his Ph.D. in 2015 with Prof. Cesare Gennari. He then joined the group of Prof. Dario Neri at ETH Zürich as a postdoctoral fellow. In 2018, he returned to Università degli Studi di Milano, where he is currently working as a research fellow. In 2019 he was awarded the Junior Prize “Organic Chemistry for Life Sciences” by the Italian Chemical Society. His research interests include the development of novel drug delivery strategies and the synthesis of ligands for clinically relevant protein targets.

Abtract:

New-generation Self-Immolative Spacers for Fast and Controlled Release of Anticancer Drugs

Topic:

Self-immolative (SI) spacers are covalent constructs capable of undergoing a spontaneous disassembly starting from a stable and inactive state, in response to specific stimuli [1]. The growing interest in the generation of stimuli-responsive devices has led to the widespread application of SI spacers in different areas, including synthetic and analytical chemistry, material sciences, and medicinal chemistry, especially in the context of prodrugs, antibody-drug conjugates, and several other drug-release strategies. We have recently described a proline-derived SI spacer that is able to release different types of anticancer drugs (possessing either a phenolic or secondary and tertiary hydroxyl groups) through a fast cyclization mechanism involving carbamate cleavage. The high efficiency of drug release obtained with this spacer was found to be beneficial for the in vitro cytotoxic activity of protease-sensitive prodrugs, compared with a commonly used spacer of the same class. Starting from these findings, novel derivatives of this proline-derived SI spacer have been designed and synthesized, either to further accelerate the drug release rates or to develop a first-in-class spacer for dual-controlled drug release. These findings expand the repertoire of degradation machineries and are instrumental for the future development of highly efficient delivery platforms.

Riccardo Marin obtained his PhD in Chemistry jointly from the University Ca’ Foscari (Venice, Italy) and the Institut National de la
Recherche Scientifique (INRS – Varénnes, Canada) under the supervision of Prof. P. Canton and Prof. F. Vetrone. He then undertook a postdoctoral fellowship at the University of Ottawa from 2017 to 2019 with Prof. E. Hemmer and Prof. M. Murugesu. He is currently a Marie Skłodowska-Curie fellow at the Universidad Autónoma de Madrid in the group of Prof. D. Jaque. His research interests encompass the development and study of optically active (nano)materials based on lanthanide ions and semiconductors.

Topic:

Infrared-emitting multimodal nanostructures for controlled in vivo magnetic hyperthermia

Abstract:

Deliberate and local increase of the temperature within solid tumours represents an effective therapeutic approach. Thermal therapies embrace this concept leveraging the capability of some species to convert the absorbed energy into heat. To that end, magnetic hyperthermia (MHT) makes use of magnetic nanoparticles that can effectively dissipate the energy absorbed under alternating magnetic fields. Indeed, MHT is one of the very few nanoparticle-based therapeutic modalities that is currently clinical trial and that has therefore the potential to be used in the clinics. However, magnetic nanoparticles cannot provide realtime thermal feedback during MHT. As a result, unwanted overheating might occur and on-the-fly adjustment of the therapeutic parameters (such as the frequency of the alternating magnetic field) is unfeasible. Accurate, rapid, and cost-effective localization of magnetic nanoparticles within a tissue represents another challenge, which could increase the efficacy and precision of MHT. In this talk, I present the combination of iron oxide magnetic nanoparticles with state-of-the-art infrared luminescent nanothermometers (Ag2S nanoparticles) in a nanocapsule that simultaneously overcomes these limitations. The novel optomagnetic nanocapsule acts as multimodal contrast agent for different imaging techniques (magnetic resonance, photoacoustic, infrared fluorescence, optical tomography, and X-ray computed tomography). Most crucially, this nanocapsule
provides accurate (0.2 ⁰C resolution) and real-time subcutaneous thermal feedback during in vivo MHT, also enabling the attainment of thermal maps of the area of interest. These findings are a milestone on the road towards controlled magnetothermal therapies with minimal side effects.

Abstract:

A novel class of small molecule degraders targeting prion protein folding intermediate

Topic:

Decades of research efforts have conclusively provided overwhelming evidence that the cellular prion protein (PrPC) represents an optimal pharmaceutical target to tackle prion diseases, a set of fatal and incurable neurodegenerative disorders characterized by the conformational conversion of the physiological PrPC into a misfolded and infectious isoform referred to as PrP scrapie (PrPSc). Indeed, PrPC plays a key role in the disease etiology and knock-out experiments demonstrated that its therapeutic suppression can be considered safe. Over the years different strategies have been proposed to tackle this target based on traditional drug discovery approaches, such as the identification of small molecules able to promote the PrPC relocalization from cellular membrane to intracellular endosomes, as well as PrPC binders that prevent its conversion to PrPSc. However no therapy is yet available, and prion disease still represents a currently unmet medical need. Very recently, we have applied a novel drug discovery approach devoted to lowering PrPC levels by hampering a complete folding process. We refer to this strategy as Pharmacological Protein Inactivation by Folding Intermediate Targeting (PPI-FIT). The reconstruction of the PrP folding pathway through all-atoms MD simulation allowed the identification of a metastable intermediate of the PrP folding pathway characterized by a druggable pocket. Virtual screening of a commercial small molecule library resulted in the identification of thirteen potential binders, four of which capable of selectively lowering the load of PrP into the cellular membrane and promote its degradation. Additionally, one of these compounds inhibits prion replication in a dose-dependent fashion.

Dr. Albert Antolin obtained a PhD in Pharmacoinformatics (Pompeu Fabra University,Spain) pioneering the application of polypharmacology prediction to chemical biology by uncovering off-targets of chemical probes. Dr. Antolin was subsequently awarded a Marie Curie Fellowship to join the Institute of Cancer Research (UK) to develop the first objective resource for the assessment of chemical probes (https://probeminer.icr.ac.uk/). Next, Dr. Antolin won a Wellcome Fellowship to explore the polypharmacology of cancer drugs and their implications for precision oncology. Having worked in industry and academia, Dr. Antolin is interested in bridging industrial drug discovery with remaining fundamental questions in cancer chemical systems biology

Abstract:

From probe to drug: Polypharmacology across drug discovery

Topic:

Most small molecules interact with several target proteins but this polypharmacology is seldom comprehensively investigated or explicitly exploited during drug discovery. Here, we present the use of computational and experimental methods to identify and systematically characterize the kinase cross-pharmacology of representative HSP90 and PARP inhibitors. We demonstrate that the HSP90 inhibitors ganetespib and luminespib and the PARP inhibitors rucaparib and niraparib display unique off-target kinase pharmacology as compared to other clinical inhibitors of the same class, with important implications for personalized prescription. We also demonstrate that the early PARP chemical tool PJ34 displays a different polypharmacology than several FDA-approved PARP inhibitors, with important implications for target validation and the practise of chemical biology. We finally demonstrate that polypharmacology evolved during the optimisation to discover luminespib and that the hit, leads and clinical candidate all have different polypharmacological profiles. We therefore recommend the computational and experimental characterization of polypharmacology earlier in drug discovery projects to unlock new multi-target drug design opportunities as well as identifying undesired toxicity and unexplained cellular effects.