Daniel Conole
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View article: Spatiotemporally resolved GPCR interactome uncovers unique mediators of receptor agonism
Spatiotemporally resolved GPCR interactome uncovers unique mediators of receptor agonism Open
Cellular signaling by membrane G protein-coupled receptors (GPCRs) is governed by a complex and diverse array of mechanisms. The dynamics of a GPCR interactome, as it evolves over time and space in response to an agonist, provide a unique …
View article: Phenotypic approaches for CNS drugs
Phenotypic approaches for CNS drugs Open
Central nervous system (CNS) drug development is plagued by high clinical failure rate. Phenotypic assays promote clinical translation of drugs by reducing complex brain diseases to measurable, clinically valid phenotypes. We critique rece…
View article: A spatiotemporally resolved GPCR interactome reveals novel mediators of receptor agonism
A spatiotemporally resolved GPCR interactome reveals novel mediators of receptor agonism Open
Summary Cellular signaling by membrane G protein-coupled receptors (GPCRs) is orchestrated by a complex and diverse array of mechanisms. The dynamics of a GPCR interactome as it evolves over time and space in response to an agonist can off…
View article: Structure-Guided Design and Optimization of Covalent VHL-Targeted Sulfonyl Fluoride PROTACs
Structure-Guided Design and Optimization of Covalent VHL-Targeted Sulfonyl Fluoride PROTACs Open
Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that have emerged as a therapeutic modality to induce targeted protein degradation (TPD) by harnessing cellular proteolytic degradation machinery. PROTACs which liga…
View article: Chemical tools for profiling the intracellular ADP-ribosylated proteome
Chemical tools for profiling the intracellular ADP-ribosylated proteome Open
6Yn-Pro is a cell-permeable proprobe successfully undergoing metabolic conversion into 6Yn-NAD + for subsequent intracellular labelling of ADP-ribosylated proteins.
View article: Discovery of potent and selective activity-based probes (ABPs) for the deubiquitinating enzyme USP30
Discovery of potent and selective activity-based probes (ABPs) for the deubiquitinating enzyme USP30 Open
IMP-2586 and IMP-2587 are selective and potent small molecule USP30 activity-based probes that engage USP30 rapidly in intact cells.
View article: Discovery of a Potent Deubiquitinase (DUB) Small‐Molecule Activity‐Based Probe Enables Broad Spectrum DUB Activity Profiling in Living Cells**
Discovery of a Potent Deubiquitinase (DUB) Small‐Molecule Activity‐Based Probe Enables Broad Spectrum DUB Activity Profiling in Living Cells** Open
Deubiquitinases (DUBs) are a family of >100 proteases that hydrolyze isopeptide bonds linking ubiquitin to protein substrates, often leading to reduced substrate degradation through the ubiquitin proteasome system. Deregulation of DUB acti…
View article: Discovery of a Potent Deubiquitinase (DUB) Small‐Molecule Activity‐Based Probe Enables Broad Spectrum DUB Activity Profiling in Living Cells**
Discovery of a Potent Deubiquitinase (DUB) Small‐Molecule Activity‐Based Probe Enables Broad Spectrum DUB Activity Profiling in Living Cells** Open
Deubiquitinases (DUBs) are a family of >100 proteases that hydrolyze isopeptide bonds linking ubiquitin to protein substrates, often leading to reduced substrate degradation through the ubiquitin proteasome system. Deregulation of DUB acti…
View article: Structure-guided design and optimization of covalent VHL-targeted sulfonyl fluoride PROTACs
Structure-guided design and optimization of covalent VHL-targeted sulfonyl fluoride PROTACs Open
Abstract Figure Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that have emerged as a therapeutic modality to induce targeted protein degradation (TPD) by harnessing cellular proteolytic degradation machinery. PR…
View article: Electrophile scanning by chemical proteomics reveals a potent pan-active DUB probe for investigation of deubiquitinase activity in live cells
Electrophile scanning by chemical proteomics reveals a potent pan-active DUB probe for investigation of deubiquitinase activity in live cells Open
Deubiquitinases (DUBs) are proteases that hydrolyze isopeptide bonds linking ubiquitin to protein substrates, which can lead to reduced substrate degradation through the ubiquitin proteasome system. Deregulation of DUB activity has been im…
View article: A Series of Substituted Bis-Aminotriazines Are Activators of the Natriuretic Peptide Receptor C
A Series of Substituted Bis-Aminotriazines Are Activators of the Natriuretic Peptide Receptor C Open
C-type natriuretic peptide (CNP) is involved in the regulation of vascular homeostasis, which is at least partly mediated through agonism of natriuretic peptide receptor C (NPR-C), and loss of this signaling has been associated with vascul…
View article: Light-mediated multi-target protein degradation using arylazopyrazole photoswitchable PROTACs (AP-PROTACs)
Light-mediated multi-target protein degradation using arylazopyrazole photoswitchable PROTACs (AP-PROTACs) Open
A new class of arylazopyrazole photoswitchable PROTACs (AP-PROTACs) enables light-triggered degradation of a specific ensemble of protein kinases.
View article: Synthesis and structure-activity relationships for a new class of tetrahydronaphthalene amide inhibitors of Mycobacterium tuberculosis
Synthesis and structure-activity relationships for a new class of tetrahydronaphthalene amide inhibitors of Mycobacterium tuberculosis Open
Drug resistant tuberculsosis (TB) is global health crisis that demands novel treatment strategies. Bacterial ATP synthase inhibitors such as bedaquiline and next-generation analogues (such as TBAJ-876) have shown promising efficacy in pati…
View article: A novel tubulin binding molecule drives differentiation of acute myeloid leukaemia cells
A novel tubulin binding molecule drives differentiation of acute myeloid leukaemia cells Open
Acute Myeloid Leukaemia (AML) continues to have a poor prognosis, especially in the elderly. One reason for this is that many treatment regimens are not well tolerated by elderly patients. Much current focus is on the development of therap…
View article: Synthesis and structure-activity relationships for tetrahydroisoquinoline-based inhibitors of Mycobacterium tuberculosis
Synthesis and structure-activity relationships for tetrahydroisoquinoline-based inhibitors of Mycobacterium tuberculosis Open
A series of 5,8-disubstituted tetrahydroisoquinolines were shown to be effective inhibitors of M. tb in culture and modest inhibitors of M. tb ATP synthase. There was a broad general trend of improved potency with higher lipophilicity. Lar…
View article: Synthetic Studies to Help Elucidate the Metabolism of the Preclinical Candidate TBAJ-876—A Less Toxic and More Potent Analogue of Bedaquiline
Synthetic Studies to Help Elucidate the Metabolism of the Preclinical Candidate TBAJ-876—A Less Toxic and More Potent Analogue of Bedaquiline Open
Bedaquiline is a novel drug approved in 2012 by the FDA for treatment of drug-resistant tuberculosis (TB). Although it shows high efficacy towards drug-resistant forms of TB, its use has been limited by the potential for significant side e…
View article: Targeting STAT3 signalling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer
Targeting STAT3 signalling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer Open
PURPOSE Estrogen receptor (ER) positive breast cancer is frequently sensitive to endocrine therapy. Multiple mechanisms of endocrine therapy resistance have been identified, including cancer stem-like cell (CSC) activity. Sulforaphane (SFN…
View article: Discovery of a novel fluorescent chemical probe suitable for evaluation of neuropilin‐1 binding of small molecules
Discovery of a novel fluorescent chemical probe suitable for evaluation of neuropilin‐1 binding of small molecules Open
Neuropilin‐1 (NRP1) is emerging as an important molecule in immune signaling where it has been shown to modulate the actions of TGF‐β1 in macrophages and regulatory T cells. The development of cost‐effective and reliable assays for NRP1 bi…
View article: Recent Developments in Cell Permeable Deubiquitinating Enzyme Activity-Based Probes
Recent Developments in Cell Permeable Deubiquitinating Enzyme Activity-Based Probes Open
Deubiquitinating enzymes (DUBs) function to remove or cleave ubiquitin from post-translationally modified protein substrates. There are about 100 known DUBs in the proteome, and their dysregulation has been implicated a number of disease s…
View article: 3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel
3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel Open
Bedaquiline is a new drug of the diarylquinoline class that has proven to be clinically effective against drug-resistant tuberculosis, but has a cardiac liability (prolongation of the QT interval) due to its potent inhibition of the cardia…
View article: Biophysical screening methods for extracellular domain peptide receptors, application to natriuretic peptide receptor C ligands
Biophysical screening methods for extracellular domain peptide receptors, application to natriuretic peptide receptor C ligands Open
Endothelium‐derived C‐type natriuretic peptide possesses cytoprotective and anti‐atherogenic functions that regulate vascular homeostasis. The vasoprotective effects of C‐type natriuretic peptide are somewhat mediated by the natriuretic pe…
View article: Chemical Instability and Promiscuity of Arylmethylidenepyrazolinone-Based MDMX Inhibitors
Chemical Instability and Promiscuity of Arylmethylidenepyrazolinone-Based MDMX Inhibitors Open
Targeting the protein-protein interaction between p53 and MDM2/MDMX (MDM4) represents an attractive anticancer strategy for the treatment of p53-competent tumors. Several selective and potent MDM2 inhibitors have been developed and entered…
View article: 6-Cyano Analogues of Bedaquiline as Less Lipophilic and Potentially Safer Diarylquinolines for Tuberculosis
6-Cyano Analogues of Bedaquiline as Less Lipophilic and Potentially Safer Diarylquinolines for Tuberculosis Open
Bedaquiline (1) is a new drug for tuberculosis and the first of the diarylquinoline class. It demonstrates excellent efficacy against TB but induces phospholipidosis at high doses, has a long terminal elimination half-life (due to its high…