A5070660539- Multiple Myeloma Research and Treatments
- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- Cancer-related Molecular Pathways
- Lipid metabolism and biosynthesis
- PI3K/AKT/mTOR signaling in cancer
- CAR-T cell therapy research
- Cancer Mechanisms and Therapy
- Chronic Myeloid Leukemia Treatments
- Hippo pathway signaling and YAP/TAZ
Humboldt-Universität zu Berlin
2022-2024
Charité - Universitätsmedizin Berlin
2020-2024
Freie Universität Berlin
2022-2024
Focus (Germany)
2021-2023
American Academy of Child and Adolescent Psychiatry
2020-2021
RELX Group (United States)
2020-2021
University Hospital Ulm
2019-2020
Janssen (United States)
2016
University of California, San Diego
2015
Cyclin-dependent kinase 6 (CDK6) is an important regulator of the cell cycle. Together with CDK4, it phosphorylates and inactivates retinoblastoma (Rb) protein.
Abstract The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide are highly effective treatments for multiple myeloma. However, virtually all patients eventually relapse due to acquired drug resistance with resistance-causing genetic alterations being found only in a small subset of cases. To identify non-genetic mechanisms resistance, we here perform integrated global quantitative tandem mass tag (TMT)-based proteomic phosphoproteomic analyses RNA sequencing five paired...
Proteolysis targeting chimeras (PROTACs) hijacking the cereblon (CRBN) E3 ubiquitin ligase have emerged as a novel paradigm in drug development. Herein we found that linker attachment points of CRBN ligands highly affect their aqueous stability and neosubstrate degradation features. This work provides blueprint for assembly future heterodimeric CRBN-based degraders with tailored properties.
A modular chemistry toolbox was developed for cereblon-directed PROTACs.
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...
Thalidomide and its analogs are molecular glues (MGs) that lead to targeted ubiquitination degradation of key cancer proteins via the cereblon (CRBN) E3 ligase. Here, we develop a direct-to-biology (D2B) approach for accelerated discovery MGs. In this platform, automated, high throughput, nano scale synthesis hundreds pomalidomide-based MGs was combined with rapid phenotypic screening, enabling an unprecedented fast identification potent CRBN-acting The small molecules were further validated...
Proteasome inhibition is a highly effective treatment for multiple myeloma (MM). However, virtually all patients develop proteasome inhibitor resistance, which associated with poor prognosis. Hyperactive small ubiquitin-like modifier (SUMO) signaling involved in both cancer pathogenesis and progression. A state of increased SUMOylation has been aggressive biology. We found that relapsed/refractory MM characterized by SUMO-high state, high expression the SUMO E1-activating enzyme (SAE1/UBA2)...
Abstract Multiple myeloma (MM) is a plasma cell malignancy of the bone marrow. Despite therapeutic advances, MM remains incurable, and better risk stratification as well new therapies are therefore highly needed. The proteome has not been systematically assessed before holds potential to uncover insight into disease biology improved prognostication in addition genetic transcriptomic studies. Here we provide comprehensive multiomics analysis including deep tandem mass tag-based quantitative...
The Petasis borono-Mannich reaction was employed for an alternative entry towards three-branched cereblon ligands. Such compounds are capabable of making multiple interactions with the protein surface and possess a suitable linker exit vector. high-affinity ligands were used to assemble prototypic new molecular glues proteolysis targeting chimeras (PROTACs) BRD4 degradation. Our results highlight importance multicomponent reactions (MCRs) in drug discovery add insights into rapidly growing...
Proteolysis targeting chimeras (PROTACs) represent a new pharmacological modality to inactivate disease-causing proteins. PROTACs operate via recruiting E3 ubiquitin ligases, which enable the transfer of tags onto their target proteins, leading proteasomal degradation. However, several ligases are validated targets themselves, inhibitor apoptosis (IAP) proteins considered druggable in cancer. Here, we report three series heterobifunctional PROTACs, consist an IAP antagonist linked either von...
BCL-2, a member of the BCL-2 protein family, is an antiapoptotic factor that regulates intrinsic pathway apoptosis. Due to its aberrant activity, it frequently implicated in haematopoietic cancers and represents attractive target for development therapeutics antagonize activity. A selective inhibitor, venetoclax, was approved treating chronic lymphocytic leukaemia, acute myeloid leukemia, other haematologic malignancies, validating as anticancer target. Since then, alternative therapeutic...
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...
Introduction of fluorine into bioactive molecules has attracted much attention in drug development. For example, tetrafluorination the phthalimide moiety immunomodulatory drugs (IMiDs) a strong beneficial effect on ability to inhibit angiogenesis. The neomorphic activity E3 ligase complexes is induced by binding IMiDs cereblon. We investigated that set eight thalidomide analogs, comprising non- and tetrafluorinated counterparts, did not induce degradation substrates (IKZF3, GSPT1, CK1α,...
Proteolysis targeting chimeras (PROTACs) represent a new pharmacological modality to inactivate disease-causing proteins. PROTACs operate via recruiting E3 ubiquitin ligases, which enables the transfer of tags onto their target proteins leading proteasomal degradation. However, several ligases are validated targets themselves, inhibitor apoptosis (IAP) considered druggable in cancer. Here, we report three series heterobifunctional PROTACs, consist an IAP antagonist linked either von...
Background: Multiple myeloma is a plasma cell malignancy of the bone marrow. Despite therapeutic advances, it remains incurable and better risk stratification as well new therapies are therefore highly needed. While genomic alterations gene expression profiles have been extensively studied that led to insights into disease biology improved prognostic models, proteome multiple has not systematically assessed. Aims: To provide comprehensive multi-omics analysis malignancies. Methods: Samples...