A5035167260- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- Multiple Myeloma Research and Treatments
- Histone Deacetylase Inhibitors Research
- Organophosphorus compounds synthesis
- Cyclopropane Reaction Mechanisms
- Click Chemistry and Applications
- Redox biology and oxidative stress
- Synthesis and Reactivity of Heterocycles
- Sulfur Compounds in Biology
- Luminescence and Fluorescent Materials
- interferon and immune responses
- Crystallography and molecular interactions
- Fluorine in Organic Chemistry
- X-ray Diffraction in Crystallography
- Carbohydrate Chemistry and Synthesis
- Crystallization and Solubility Studies
- Chemical Synthesis and Characterization
- Cybersecurity and Information Systems
- Sulfur-Based Synthesis Techniques
- Kruppel-like factors research
- Enzyme Structure and Function
- CAR-T cell therapy research
- Space Science and Extraterrestrial Life
University of Dundee
2018-2025
Target (United States)
2025
AstraZeneca (United Kingdom)
2022
Charles University
2016-2019
Lomonosov Moscow State University
2011-2016
Moscow State University
2014
Leucine-rich repeat kinase 2 (LRRK2) is one of the most promising targets for Parkinson's disease. LRRK2-targeting strategies have primarily focused on type 1 inhibitors, which, however, limitations as inhibited protein can interfere with natural mechanisms, which could lead to undesirable side effects. Herein, we report development LRRK2 proteolysis targeting chimeras (PROTACs), culminating in discovery degrader XL01126, an alternative strategy. Initial designs and screens PROTACs based...
Abstract The Src homology 2 (SH2) domain recognizes phosphotyrosine (pY) post translational modifications in partner proteins to trigger downstream signaling. Drug discovery efforts targeting the SH2 domains have long been stymied by poor drug-like properties of phosphate and its mimetics. Here, we use structure-based design target E3 ligase suppressor cytokine signaling (SOCS2). Starting from highly ligand-efficient pY amino acid, a fragment growing approach reveals covalent modification...
Abstract Small molecule degraders of disease-driving proteins offer a clinically proven modality with enhanced therapeutic efficacy and the potential to tackle previously undrugged targets. Thermodynamically stable kinetically long-lived degrader-mediated ternary complexes can drive faster, more profound durable target degradation, however mechanistic features by which they impact on ubiquitination remain elusive. Here, we solve cryo-EM structures VHL Cullin 2 RING E3 ligase complexed...
Abstract Despite the development of new targeted and immune therapies, prognosis metastatic melanoma remains bleak. Therefore, it is critical to better understand mechanisms controlling advanced develop more effective treatment regimens. Hedgehog/GLI (HH/GLI) signaling inhibitors targeting central pathway transducer Smoothened (SMO) have shown be clinical efficacious in skin cancer; however, several non-canonical HH/GLI activation limit their efficacy. Here, we identify a novel SOX2-BRD4...
Small-molecule degraders of disease-driving proteins offer a clinically proven modality with enhanced therapeutic efficacy and potential to tackle previously undrugged targets. Stable long-lived degrader-mediated ternary complexes drive fast profound target degradation; however, the mechanisms by which they affect ubiquitination remain elusive. Here, we show cryo-EM structures VHL Cullin 2 RING E3 ligase degrader MZ1 directing protein Brd4 BD2 toward UBE2R1-ubiquitin, Lys 456 at optimal...
Abstract Methionine sulfoxide reductase A (MsrA) is an enzyme involved in redox balance and signaling, its aberrant activity implicated a number of diseases (for example, Alzheimer's disease cancer). Since there no simple small molecule tool to monitor MsrA real time vivo, we aimed at developing one. We have designed BODIPY‐based probe called ( S )‐Sulfox‐1, which equipped with reactive moiety. Upon reduction model E. coli ), it exhibits bathochromic shift the fluorescence maximum. This...
Abstract The suppressor of cytokine signaling 2 (SOCS2) acts as substrate recognition subunit a Cullin5 E3 ubiquitin ligase complex. SOCS2 binds to phosphotyrosine-modified epitopes degrons for ubiquitination and proteasomal degradation, yet the molecular basis has remained elusive. Here, we report co-crystal structures SOCS2-ElonginB-ElonginC in complex with phosphorylated peptides from substrates growth hormone receptor (GHR-pY595) erythropoietin (EpoR-pY426) at 1.98 Å 2.69 Å,...
Proteolysis targeting chimera (PROTAC) degraders are typically bifunctional with one moiety of an E3 ligase ligand connected to target protein via a linker. While augmented valency has been shown trivalent PROTACs two binding sites within given protein, or used recruit different targets, the possibility recruiting ligases same compound not demonstrated. Here we present dual-ligase recruitment as strategy enhance targeted degradation. We designed heterotrivalent composed CRBN, VHL and BET...
This review comprehensively covers the currently available synthetic routes to 3(5)-phosphonylated pyrazoles. There are demonstrated significant advances in this field over last 10–15 years caused by use of Bestmann–Ohira reagent [as well as (diazomethyl)phosphonates and phosphonylated hydrazonoyl halides] reactions with diverse dipolarophiles. 1,3-Dipolar cycloaddition diazo compounds α,β-unsaturated phosphonates intramolecular heterocyclization (1-diazoallyl)phosphonates...
The bromodomain and extra-terminal (BET) family of proteins includes BRD2, BRD3, BRD4, the testis-specific protein, BRDT, each containing two N-terminal tandem (BRD) modules. Potent selective inhibitors targeting bromodomains are required to elucidate their biological role(s), with potential clinical applications. In this study, we designed synthesized a series benzimidazole-6-sulfonamides starting from azobenzene compounds MS436 (7 a) MS611 b) that exhibited preference for first (BD1) over...
1-Substituted vinylphosphonates could serve as convenient precursors for functionalized pyrazoles in condition-controlled 1,3-dipolar cycloaddition reactions.
Abstract Methionine sulfoxide reductase A (MsrA) is an enzyme involved in redox balance and signaling, its aberrant activity implicated a number of diseases (for example, Alzheimer's disease cancer). Since there no simple small molecule tool to monitor MsrA real time vivo, we aimed at developing one. We have designed BODIPY‐based probe called ( S )‐Sulfox‐1, which equipped with reactive moiety. Upon reduction model E. coli ), it exhibits bathochromic shift the fluorescence maximum. This...
Proteolysis targeting chimera (PROTAC) degraders are typically bifunctional with one E3 ligase ligand connected to target protein via a linker. While augmented valency has been shown trivalent PROTACs two binding sites within given protein, or used recruit different targets, the possibility of recruiting ligases same compound not demonstrated. Here we present dual-ligase recruitment as strategy enhance targeted degradation. We designed heterotrivalent composed CRBN, VHL and BET ligands,...
Nonenzymatic oxidative processes in living organisms are among the inevitable consequences of respiration and environmental conditions. These can lead to formation two stereoisomers (R S) methionine sulfoxide, redox balance between sulfoxide proteins has profound implications on their function. Methionine oxidation be reverted enzymatically by reductases (Msrs). The enzyme classes known fulfill this role MsrA, reducing (S)-isomer, MsrB, (R)-isomer sulfoxide. They strictly stereoselective...
Abstract The suppressor of cytokine signaling 2 (SOCS2) acts as substrate recognition subunit a Cullin5 E3 ubiquitin ligase complex. SOCS2 binds to phosphotyrosine-modified epitopes degrons for ubiquitination and proteasomal degradation, yet the molecular basis has remained elusive. We solved co-crystal structures SOCS2-ElonginB-ElonginC in complex with phosphorylated peptides from substrates growth hormone receptor (GHR-pY595) erythropoietin (EpoR-pY426) at 1.98 Å 2.69 Å, respectively. Both...
A series of 2-aryl-substituted 1-aminocyclopropylphosphonates containing an additional remote phosphonate group have been synthesized starting from readily accessible dimethyl (1<i>R</i>*,2<i>R</i>*)-2-(4-bromophenyl)-1-formamidocyclopropylphosphonate using cross-coupling methodology. Different types palladium-catalyzed reactions for carbon–carbon and carbon–phosphorus bond formation were realized. In each case the optimum conditions found to obtain desired products in high yield both small-...
Leucine Rich Repeat Kinase 2 (LRRK2) is one of the most promising targets for Parkinson’s Disease. LRRK2 targeting strategies have primarily focused on Type 1 kinase inhibitors, which however limitations as inhibited pro-tein can interfere with natural mechanisms could lead to undesirable side effects. Herein, we report devel-opment Proteolysis Targeting Chimeras (PROTACs), culminating in discovery degrader XL01126, an alternative strategy. Initial designs and screens PROTACs based ligands...
The Src homology 2 (SH2) domain is present in many proteins that bind to phosphotyrosine (pY) post translational modifications partner trigger downstream signalling. Since pY-driven protein-protein interactions can sustain disease, SH2 domains have long been the focus of small-molecule ligand discovery efforts, but stymied by poor drug-like properties phosphate and its mimetics. Here, we used structure-based design target suppressor cytokine signalling (SOCS2) – substrate recognition subunit...
Biological oxidation of methionine side chains in proteins is a process that affects the functions many proteins. One key regulators this signaling enzyme sulfoxide reductase A (MsrA). MsrA implicated number diseases, but detailed understanding its function hindered by lack tools for monitoring enzyme’s activity. We have designed and synthesized probe named (S,S)-Sulfox-2 based on BODIPY fluorophore equipped with two chiral units defined stereochemistry. shown to be highly responsive allows...
The Src homology 2 (SH2) domain recognises phosphotyrosine (pY) post translational modifications in partner proteins to trigger downstream signalling. Drug discovery efforts targeting the SH2 domains have long been stymied by poor drug-like properties of phosphate and its mimetics. Here, we used structure-based design target E3 ligase suppressor cytokine signalling (SOCS2). Starting from highly ligand-efficient pY amino acid, a fragment growing approach led serendipitous observation covalent...