A5051873783- Cancer-related Molecular Pathways
- Cancer Immunotherapy and Biomarkers
- Protein Structure and Dynamics
- Click Chemistry and Applications
- Chemical Synthesis and Analysis
- CAR-T cell therapy research
- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- Enzyme Structure and Function
- Monoclonal and Polyclonal Antibodies Research
- Microtubule and mitosis dynamics
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Cellular Mechanics and Interactions
- Advanced NMR Techniques and Applications
- RNA modifications and cancer
- Molecular spectroscopy and chirality
- NMR spectroscopy and applications
- Glycosylation and Glycoproteins Research
- Immunotherapy and Immune Responses
- Protein Degradation and Inhibitors
- Force Microscopy Techniques and Applications
- Advanced Fluorescence Microscopy Techniques
- Microbial Natural Products and Biosynthesis
- Computational Drug Discovery Methods
Jagiellonian University
2015-2024
Max Planck Institute of Biochemistry
2009-2020
Krakow Cardiovascular Research Institute
2017
Max Planck Society
2005-2014
University of Groningen
2014
University of Pittsburgh
2009
Technical University of Munich
2006
University of Regensburg
2003
Scripps Research Institute
2003
University of Toronto
2003
// Krzysztof M. Zak 1,2 , Przemyslaw Grudnik 2 Katarzyna Guzik 3 Bartosz J. Zieba 1,3 Bogdan Musielak Alexander Dömling 4 Grzegorz Dubin and Tad A. Holak 1,3,5 1 Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa, Krakow, Poland Faculty Biochemistry, Biophysics Department Organic Chemistry, Ingardena, for Drug Design, University Groningen, Deusinglaan The Netherlands 5 Max Planck Institute Am Klopferspitz, Martinsried, Germany Correspondence to: Dubin, email:...
Blockade of the PD-1/PD-L1 immune checkpoint pathway with monoclonal antibodies has provided significant advances in cancer treatment. The antibody-based immunotherapies carry a number disadvantages such as high cost antibodies, their limited half-life, and immunogenicity. Development small-molecule inhibitors that could overcome these drawbacks is slow because incomplete structural information for this pathway. first chemical have been recently disclosed by Bristol-Myers Squibb. Here we...
Mdm2 is a major negative regulator of the tumor suppressor p53 protein, protein that plays crucial role in maintaining genome integrity. Inactivation most prevalent defect human cancers. Inhibitors Mdm2–p53 interaction restore functional constitute potential nongenotoxic anticancer agents with novel mode action. We present here 2.0 Å resolution structure bound stapled peptide. Such peptides, which are conformationally and proteolytically stabilized all-hydrocarbon staples, an emerging class...
Antibodies targeting the PD-1/PD-L1 immune checkpoint achieved spectacular success in anticancer therapy recent years. In contrast, no small molecules with cellular activity have been reported so far. Here we provide evidence that are capable of alleviating checkpoint-mediated exhaustion Jurkat T-lymphocytes. The two optimized small-molecule inhibitors interaction, BMS-1001 and BMS-1166, developed by Bristol-Myers Squibb, bind to human PD-L1 block its interaction PD-1, when tested on...
The oncoprotein MDM2 inhibits the tumor suppressor protein p53 by binding to transactivation domain. gene is inactivated in many human tumors either mutations or oncogenic proteins. In some tumors, such as soft tissue sarcomas, overexpression of inactivates an otherwise intact p53, disabling genome integrity checkpoint and allowing cell cycle progression defective cells. Disruption MDM2/p53 interaction leads increased levels restored transcriptional activity, indicating restoration check...
Intensive anticancer drug discovery efforts have been made to develop small molecule inhibitors of the p53-MDM2 and p53-MDMX interactions. We present here structures most potent bound MDM2 MDMX that are based on new imidazo-indole scaffold. In addition, structure recently reported spiro-oxindole inhibitor is described. The indicate how substituents a bind three subpockets MDM2/X-p53 interaction should be optimized for effective binding and/or MDMX. While triggers significant ligand-induced...
Abstract Blockade of the immunoinhibitory PD‐1/PD‐L1 pathway using monoclonal antibodies has shown impressive results with durable clinical antitumor responses. Anti‐PD‐1 and anti‐PD‐L1 have now been approved for treatment a number tumor types, whereas development small molecules targeting immune checkpoints lags far behind. We characterized two classes macrocyclic‐peptide inhibitors directed at pathway. show that these macrocyclic compounds act by directly binding to PD‐L1 they are capable...
The parallel discovery of multiple scaffolds useful to antagonize the cancer-relevant protein–protein interaction p53/Hdm2 is described. new method based on tightly interwoven interplay multicomponent reaction chemistry, structural biology, computational and high-content NMR-based screening. Detailed facts importance specialist readers are published as "Supporting Information". Such documents peer-reviewed, but not copy-edited or typeset. They made available submitted by authors. Please...
CA-170 is currently the only small-molecule modulator in clinical trials targeting PD-L1 and VISTA proteins – important negative checkpoint regulators of immune activation. The reported therapeutic results to some extent mimic those FDA-approved monoclonal antibodies overcoming limitations high production costs adverse effects latter. However, no conclusive biophysical evidence proving binding hPD-L1 has ever been presented. Using well-known vitro methods: NMR assay, HTRF cell-based...
A series of C2-symmetric inhibitors was designed and evaluated for inhibitory activity against the programmed cell death-1/programmed death-ligand 1(PD-1/PD-L1) protein-protein interaction (PPI) in a homogenous time-resolved fluorescence (HTRF) assay PD-1 signaling cell-based coculture assays. 2a (LH1306) 2b (LH1307) exhibited IC50 values 25 3.0 nM, respectively, HTRF assay. While ∼3.8-fold more potent than previously reported inhibitor 1a, could not be differentiated from 1b due to their...
We describe a new class of potent PD-L1/PD-1 inhibitors based on terphenyl scaffold that is derived from the rigidified biphenyl-inspired structure. Using in silico docking, we designed and then experimentally demonstrated effectiveness terphenyl-based scaffolds inhibiting PD-1/PD-L1 complex formation using various biophysical biochemical techniques. also present high-resolution structure PD-L1 with one our most to identify key PD-L1/inhibitor interactions at molecular level. In addition,...