A5060479155- Protein Degradation and Inhibitors
- Histone Deacetylase Inhibitors Research
- Peptidase Inhibition and Analysis
- Multiple Myeloma Research and Treatments
- Click Chemistry and Applications
- Asthma and respiratory diseases
- Pediatric health and respiratory diseases
- Ubiquitin and proteasome pathways
- IL-33, ST2, and ILC Pathways
- Chemical Synthesis and Analysis
- Cancer-related gene regulation
University of Bonn
2023-2025
Medizinische Hochschule Hannover
2017
Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomide are the most common cereblon (CRBN) recruiters in proteolysis-targeting chimera (PROTAC) design. However, these CRBN ligands induce degradation of IMiD neosubstrates inherently unstable, degrading hydrolytically under moderate conditions. In this work, we simultaneously optimized physiochemical properties, stability, on-target affinity, off-target neosubstrate modulation features to develop novel...
Histone deacetylases (HDACs) play a key role in the control of transcription, cell proliferation, and migration. FDA-approved histone deacetylase inhibitors (HDACi) demonstrate clinical efficacy treatment different T-cell lymphomas multiple myeloma. However, due to unselective inhibition, they display wide range adverse effects. One approach avoiding off-target effects is use prodrugs enabling controlled release inhibitor target tissue. Herein, we describe synthesis biological evaluation...
Proteolysis-targeting chimeras (PROTACs) have recently gained popularity as targeted protein degradation (TPD) promises to overcome the limitations of occupancy-driven pharmacology. However, most degraders rely on a small number E3 ligases. In this study, we present first-in-class histone deacetylase (HDAC) PROTACs recruiting DDB1- and CUL4- associated factor 11 (DCAF11). We established synthesis route entirely solid-phase prepare set eleven degraders. The long flexible spacer bearing FF2039...
Targeted protein degradation (TPD) represents a promising alternative to conventional occupancy-driven inhibition. Despite the existence of more than 600 E3 ligases in human proteome, so far only few have been utilized for TPD histone deacetylases (HDACs), which represent important epigenetic anticancer drug targets. In this study, we disclose first-in-class Fem-1 homologue B (FEM1B)-recruiting HDAC degraders. A set 12 proteolysis targeting chimeras (PROTACs) was synthesized using...
Histone deacetylases (HDACs) are promising targets for epigenetic drug discovery. Additionally, targeted degradation of HDACs has emerged as a novel approach in medicinal chemistry and chemical biology. However, most inhibitors degraders rely on the potentially genotoxic hydroxamate zinc-binding group (ZBG). In this study, we present development HDAC6-directed proteolysis-targeting chimeras (PROTACs) featuring an ethyl hydrazide moiety alternative ZBG. This avoids genotoxicity concerns...
Histone deacetylases (HDACs) are promising targets for epigenetic drug discovery. Additionally, targeted degradation of HDACs has emerged as a novel approach in medicinal chemistry and chemical biology. However, most inhibitors degraders rely on the potentially genotoxic hydroxamate zinc-binding group (ZBG). In this study, we present development HDAC6-directed proteolysis-targeting chimeras (PROTACs) featuring an ethyl hydrazide moiety alternative ZBG. This avoids genotoxicity concerns...
Proteolysis-targeting chimeras (PROTACs) have recently gained popularity as targeted protein degradation (TPD) promises to overcome the limitations of occupancy-driven pharmacology. However, most degraders rely on a small number E3 ligases. In this study, we present first-in-class histone deacetylase (HDAC) PROTACs recruiting DDB1- and CUL4- associated factor 11 (DCAF11). We established synthesis route entirely solid-phase prepare set eleven degraders. The long flexible spacer bearing FF2039...
Histone deacetylases (HDACs) are promising targets for epigenetic drug discovery. Additionally, targeted degradation of HDACs has emerged as a novel approach in medicinal chemistry and chemical biology. However, most inhibitors degraders rely on the potentially genotoxic hydroxamate zinc-binding group (ZBG). In this study, we present development HDAC6-directed proteolysis-targeting chimeras (PROTACs) featuring an ethyl hydrazide moiety alternative ZBG. This avoids genotoxicity concerns...
Proteolysis‐targeting chimeras (PROTACs) have recently gained popularity as targeted protein degradation (TPD) promises to overcome the limitations of occupancy‐driven pharmacology. However, most degraders rely on a small number E3 ligases. In this study, we present first‐in‐class histone deacetylase (HDAC) PROTACs recruiting DDB1‐ and CUL4‐ associated factor 11 (DCAF11). We established synthesis route entirely solid‐phase prepare set eleven degraders. The long flexible spacer bearing FF2039...
There is a growing interest in alternative strategies for targeted protein degradation. In this work, we present the development of histone deacetylase (HDAC) degraders based on hydrophobic tagging technology. To end, library hydrophobically tagged HDAC inhibitors was synthesized via efficient solid-phase protocols utilizing pre-loaded resins. The subsequent biological evaluation led to identification our best degrader, 1a, which significantly decreased HDAC1 levels MM.1S multiple myeloma cells.
Because Th17-polarized airway inflammation correlates with poor control in bronchial asthma and is a feature of numerous other difficult-to-treat inflammatory lung diseases, new therapeutic approaches for this type are necessary. We assessed different licensed anti-inflammatory agents known or expected efficacy against Th17-polarization mouse models Th17-dependent inflammation. Upon intravenous transfer vitro derived Th17 cells intranasal challenge the corresponding antigen, we established...
Multi-target drugs (MTDs) are emerging alternatives to combination therapies. Since both histone deacetylases (HDACs) and cyclooxygenase-2 (COX-2) known be overexpressed in several cancer types, we herein report the design, synthesis, biological evaluation of a library dual HDAC-COX inhibitors. The designed compounds were synthesized via an efficient parallel synthesis approach using preloaded solid-phase resins. Biological vitro assays demonstrated that possess pronounced inhibitory...
Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomide represent the most typical cereblon (CRBN) recruiters that are frequently utilized in proteolysis-targeting chimera (PROTAC) design. These CRBN binders, however, cause degradation of IMiD neosubstrates innately unstable they undergo hydrolytic under mild conditions. Here we present systematic approach towards novel non-phthalimide binders were obtained via simultaneous optimization their physiochemical...
Our previously reported HDAC6 inhibitor (HDAC6i) Marbostat-100 (4) has provided many arguments for further clinical evaluation. By the substitution of acidic hydrogen 4 different carbon residues, we were able to generate an all-carbon stereocenter, which significantly improves hydrolytic stability inhibitor. Further asymmetric synthesis shown that (S)-configured inhibitors preferentially bind HDAC6. This led highly selective and potent methyl-substituted derivative S-29b, elicited a...
Targeted protein degradation (TPD) represents a promising alternative to conventional occupancy-driven inhibition. Despite the existence of more than 600 E3 ligases in human proteome, so far only few have been utilized for TPD histone deacetylases (HDACs), which represent important epigenetic anticancer drug targets. In this study, we disclose first-in-class Fem-1 homolog B (FEM1B)-recruiting HDAC degraders. A set twelve proteolysis targeting chimeras (PROTACs) was synthesized using...