A5088542812- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Cancer-related Molecular Pathways
- Cancer Immunotherapy and Biomarkers
- Click Chemistry and Applications
- CAR-T cell therapy research
- Peptidase Inhibition and Analysis
- Synthesis and Biological Evaluation
- Chemical Synthesis and Analysis
- Ubiquitin and proteasome pathways
- Monoclonal and Polyclonal Antibodies Research
- Protein Degradation and Inhibitors
- Crystallography and molecular interactions
- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- Synthesis of Tetrazole Derivatives
- Microtubule and mitosis dynamics
- Protein Structure and Dynamics
- RNA modifications and cancer
- Cancer therapeutics and mechanisms
- HIV Research and Treatment
- Signaling Pathways in Disease
- DNA Repair Mechanisms
- Lung Cancer Research Studies
- Molecular Spectroscopy and Structure
Jagiellonian University
2016-2024
University of Groningen
2016
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,...
The PD-1/PD-L1 axis has proven to be a highly efficacious target for cancer immune checkpoint therapy with several approved antibodies. Also, small molecules based on biphenyl core can antagonize PD-1/PD-L1, leading the in vitro formation of PD-L1 dimers. However, their development remains challenging, as we do not yet fully understand mode action. In this work, designed new scaffold our previously solved high-resolution structures low-molecular-weight inhibitors bound PD-L1. A compound...
Abstract Stapled peptides are chemical entities in‐between biologics and small molecules, which have proven to be the solution high affinity protein–protein interaction antagonism, while keeping control over pharmacological performance such as stability membrane penetration. We demonstrate that multicomponent reaction‐based stapling is an effective strategy for development of α‐helical with highly potent dual antagonistic action MDM2 MDMX binding p53. Such a inhibitory activity p53‐MDM2/X...
Targeting the programmed cell death protein 1/programmed 1 ligand (PD-1/PD-L1) interaction has become an established strategy for cancer immunotherapy. Although hundreds of small-molecule, peptide, and peptidomimetic inhibitors have been proposed in recent years, only a limited number drug candidates show good PD-1/PD-L1 blocking activity cell-based assays. In this article, we compare representative molecules from different classes terms their dissociation capacity measured by HTRF vitro...
The p53 pathway is inactivated in almost all types of cancer by mutations the encoding gene or overexpression negative regulators, Mdm2 and/or Mdmx. Restoration function inhibition p53-Mdm2/Mdmx interaction opens up a prospect for nongenotoxic anticancer therapy. Here, we present syntheses, activities, and crystal structures two novel classes Mdm2-p53 inhibitors that are based on 3-pyrrolin-2-one 2-furanone scaffolds. complexes formed these reveal dimeric protein molecular organization has...
Development of small molecules targeting the PD-L1/PD-1 interface is advancing both in industry and academia, but only a few have reached early-stage clinical trials. Here, we take closer look at general druggability PD-L1 using silico hot spot mapping nuclear magnetic resonance (NMR)-based characterization. We found that conformational elasticity surface strongly influences formation spots. deconstructed several generations known inhibitors into fragments examined their binding properties...
Although heavily studied, the subject of anti-PD-L1 small-molecule inhibitors is still elusive. Here we present a systematic overview principles behind successful inhibitor design on example m-terphenyl scaffold, with particular focus neglected influence solubilizer tag overall affinity toward PD-L1. The developed according to proposed guidelines was characterized through its potency in blocking PD-1/PD-L1 complex formation homogeneous time-resolved fluorescence and cell-based assays. also...
The p53 protein is engaged in the repair of DNA mutations and elimination heavily damaged cells, providing anticancer protection. Dysregulation activity a crucial step carcinogenesis. This dysregulation often caused by overexpression negative regulators p53, among which MDM2 most prominent one. Antagonizing with small molecules restores wild-type (p53wt ) cells thus provides positive outcomes treatment p53wt cancers. Previously, we have reported discovery panel fluoro-substituted...
Macrocycles were designed to antagonize the protein–protein interaction p53-MDM2 based on three-finger pharmacophore F 19 W 23 L 25 . The synthesis was accomplished by a rapid, one-pot of indole-based macrocycles Ugi macrocyclization. reaction 12 different α,ω-amino acids and indole-3-carboxaldehyde derivatives afforded unique library otherwise difficult access. Screening for inhibition fluorescence polarization 1 H, 15 N HSQC NMR measurements confirm MDM2 binding.
Abstract Nutlin‐3a is a reversible inhibitor of the p53/MDM2 interaction. We have synthesized derivative Nutlin‐3a‐aa bearing an additional exocyclic methylene group in piperazinone moiety. more active than against purified wild‐type MDM2, and effective at increasing p53 levels releasing transcription target genes from MDM2‐induced repression. X‐ray analysis MDM2‐bound indicated that orientation its modified ring was altered comparison to Nutlin‐3a, with pointing away protein surface. Our...
The PD-1/PD-L1 complex is an immune checkpoint responsible for regulating the natural response, but also allows tumors to escape surveillance. Inhibition of axis positively contributes efficacy cancer treatment. only available therapeutics targeting are monoclonal antibody-based drugs, which have several limitations. Therefore, small molecule compounds emerging as attractive alternative that can potentially overcome drawbacks mAb-based therapy. In this article, we present a novel class based...
In this work, we present the comparison study of guanine and cytosine crystals based on hydrogen bond (HB) dynamics. The ab initio molecular dynamics gave us a base for detailed analysis. analysis trajectories by power spectrum generation, as well fluctuation interaction energies, showed large differences between HB networks in considered crystals. charge flow is molecule which forms flat surfaces zigzag structure, blocked. energy significantly less stabilizing structure than guanine....
New biphenyl-based chimeric compounds containing pomalidomide were developed and evaluated for their activity to inhibit degrade the programmed cell death-1/programmed death- ligand 1 (PD-1/PD-L1) complex. Most of displayed excellent inhibitory against PD-1/PD-L1, as assessed by homogenous time-resolved fluorescence (HTRF) binding assay. Among them, compound 3 is one best with an IC50 value 60 nM. Using ex vivo PD-1/PD-L1 blockade line bioassay that expresses human PD-1 PD-L1, we show 4 5...
Abstract Stapled peptides are chemical entities in‐between biologics and small molecules, which have proven to be the solution high affinity protein–protein interaction antagonism, while keeping control over pharmacological performance such as stability membrane penetration. We demonstrate that multicomponent reaction‐based stapling is an effective strategy for development of α‐helical with highly potent dual antagonistic action MDM2 MDMX binding p53. Such a inhibitory activity p53‐MDM2/X...
The progress in cancer survival and treatment has witnessed a remarkable transformation through the innovative approach of targeting inhibitory immune checkpoint protein PD-1/PD-L1 complex by mAbs,
By binding to the spliceosomal protein Snu66, human ubiquitin-like Hub1 is a modulator of spliceosome performance and facilitates alternative splicing. Small molecules that bind would be interest study protein-protein interaction Hub1/Snu66, which linked several pathologies, such as hypercholesterolemia, premature aging, neurodegenerative diseases, cancer. To identify small molecule ligands for Hub1, we used interface analysis, peptide modeling Hub1/Snu66 fragment-based NMR screening....