https://hdl.handle.net/20.500.11811/666 Wed, 15 Apr 2026 04:19:31 GMT 2026-04-15T04:19:31Z https://hdl.handle.net/20.500.11811/13551 Structure-affinity and structure-residence time relationships of macrocyclic Gα_q protein inhibitors Voss, Jan H.; Crüsemann, Max; Bartling, Christian R.O.; Kehraus, Stefan; Inoue, Asuka; König, Gabriele M.; Strømgaard, Kristian; Müller, Christa E. The macrocyclic depsipeptides YM-254890 (YM) and FR900359 (FR) are potent inhibitors of Gα_q/11 proteins. They are important pharmacological tools and have potential as therapeutic drugs. The hydrogenated, tritium-labeled YM and FR derivatives display largely different residence times despite similar structures. In the present study we established a competition-association binding assay to determine the dissociation kinetics of unlabeled Gα_q protein inhibitors. Structure-affinity and structure-residence time relationships were analyzed. Small structural modifications had a large impact on residence time. YM and FR exhibited 4- to 10-fold higher residence times than their hydrogenated derivatives. While FR showed pseudo-irreversible binding, YM displayed much faster dissociation from its target. The isopropyl anchor present in FR and some derivatives was essential for slow dissociation. These data provide a basis for future drug design toward modulating residence times of macrocyclic Gα_q protein inhibitors, which has been recognized as a crucial determinant for therapeutic outcome. Fri, 21 Apr 2023 00:00:00 GMT https://hdl.handle.net/20.500.11811/13551 2023-04-21T00:00:00Z https://hdl.handle.net/20.500.11811/12817 Development of the first geldanamycin-based HSP90 degraders Wurnig, Silas; Vogt, Melina; Hogenkamp, Julian; Dienstbier, Niklas; Borkhardt, Arndt; Bhatia, Sanil; Hansen, Finn Despite the early clinical promise, adverse events such as acquired resistance and dose-limiting toxicities have barred the widespread use of HSP90 inhibitors as anticancer drugs. A new approach involving proteolysis-targeting chimeras (PROTACs) to degrade the protein instead of inhibiting it may overcome these problems. In this work, we describe the design, synthesis, and evaluation of cereblon-recruiting geldanamycin-based HSP90 degraders based on the PROTAC technology. Our best degrader, 3a, effectively decreased HSP90α and HSP90β levels in cells utilizing the ubiquitin–proteasome pathway. Wed, 28 Jun 2023 00:00:00 GMT https://hdl.handle.net/20.500.11811/12817 2023-06-28T00:00:00Z https://hdl.handle.net/20.500.11811/12816 A Systematic Database Approach to Identify Companion Diagnostic Testing in Clinical Trials under the New In Vitro Diagnostic Medical Devices Regulation Wollenhaupt, Clara; Sudhop, Thomas; Knoess, Werner The European Union In Vitro Diagnostic Medical Devices Regulation (EU) 2017/746 (IVDR) introduces companion diagnostics (CDx) as a new legal term. CDx are applied in combination with a medicinal product to identify patient subgroups most likely to benefit from a treatment or who are at increased risk. This new regulation came into full effect on 26 May 2022 and represents the current development in personalized medicine. The implementation of IVDR and CDx is a regulatory challenge in the EU, requiring re-assessment of in vitro diagnostic medical devices (IVD) in terms of their CDx designation. To retrospectively identify IVD biomarker testing applied in clinical trials, a systematic search in the German PharmNet Clinical Trials database was developed. In total 3643 clinical trials conducted between 2004 and 2022 were identified. The results were analyzed in terms of medicinal products, biomarkers, and IVDs. Patient stratification based on biomarker testing mainly takes place in oncology-related trials, and the biomarkers most frequently tested are PD-L1 and HER2. Furthermore, there is a significant overlap between the collected data and non-European national authorities that have already implemented the CDx concept. This analysis could be indicatory of the medicinal products and corresponding IVD tests that could be CDx candidates under the IVDR. Mon, 12 Jun 2023 00:00:00 GMT https://hdl.handle.net/20.500.11811/12816 2023-06-12T00:00:00Z https://hdl.handle.net/20.500.11811/10805 Irreversible Antagonists for the Adenosine A2B Receptor Temirak, Ahmed; Schlegel, Jonathan; Voss, Jan; Vaaßen, Victoria; Vielmuth, Christin; Claff, Tobias; Müller, Christa Blockade of the adenosine A2B receptor (A2BAR) represents a potential novel strategy for the immunotherapy of cancer. In the present study, we designed, synthesized, and characterized irreversible A2BAR antagonists based on an 8-p-sulfophenylxanthine scaffold. Irreversible binding was confirmed in radioligand binding and bioluminescence resonance energy transfer(BRET)-based Gα15 protein activation assays by performing ligand wash-out and kinetic experiments. p-(1-Propylxanthin-8-yl)benzene sulfonyl fluoride (6a, PSB-21500) was the most potent and selective irreversible A2BAR antagonist of the present series with an apparent Ki value of 10.6 nM at the human A2BAR and >38-fold selectivity versus the other AR subtypes. The corresponding 3-cyclopropyl-substituted xanthine derivative 6c (PSB-21502) was similarly potent, but was non-selective versus A1- and A2AARs. Attachment of a reactive sulfonyl fluoride group to an elongated xanthine 8-substituent (12, Ki 7.37 nM) resulted in a potent, selective, reversibly binding antagonist. Based on previous docking studies, the lysine residue K2697.32 was proposed to react with the covalent antagonists. However, the mutant K269L behaved similarly to the wildtype A2BAR, indicating that 6a and related irreversible A2BAR antagonists do not interact with K2697.32. The new irreversible A2BAR antagonists will be useful tools and have the potential to be further developed as therapeutic drugs. Mon, 13 Jun 2022 00:00:00 GMT https://hdl.handle.net/20.500.11811/10805 2022-06-13T00:00:00Z