A5050142735- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- Multiple Myeloma Research and Treatments
- Chromatin Remodeling and Cancer
- Cancer Mechanisms and Therapy
- HIV Research and Treatment
- Ion Channels and Receptors
- Neuroscience and Neuropharmacology Research
- Inflammatory mediators and NSAID effects
- Ion channel regulation and function
- Retinoids in leukemia and cellular processes
- Neurogenesis and neuroplasticity mechanisms
- Estrogen and related hormone effects
- Neuroblastoma Research and Treatments
- Cellular transport and secretion
- Peroxisome Proliferator-Activated Receptors
- Software Testing and Debugging Techniques
- Cancer, Stress, Anesthesia, and Immune Response
University of Dundee
2018-2024
ORCID
2020
Newcastle University
2013-2018
Bifunctional degrader molecules, known as proteolysis-targeting chimeras (PROTACs), function by recruiting a target to an E3 ligase, forming target/PROTAC/ligase ternary complex. Despite the importance of this key intermediate species, no detailed validation method directly determine binding parameters for complex kinetics has been reported, and it remains be addressed whether tuning PROTAC complexes may effective strategy improve efficiency targeted protein degradation. Here, we develop...
Abstract Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target E3 ligase, resulting in ubiquitylation proteosome-dependent target. In clinic, oral route administration is option choice but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed achieve orally...
Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors. Guided by biophysical and structural studies of ternary complexes, we designed a heterobifunctional small molecule potently degrades 13 out 17 most alleles. Compared inhibition, degradation...
Targeted protein degradation has recently emerged as a novel option in drug discovery. Natural half-life is expected to affect the efficacy of degrading agents, but what extent it influences target not been systematically explored. Using simple mathematical modeling degradation, we find that natural dramatic effect on level induced by degrader agent which can pose significant hurdles screening efforts. Moreover, show upon for degraders short-lived proteins, agents stall synthesis, such GSPT1...
Summary Targeted protein degradation has recently emerged as a novel option in drug discovery. Natural half-life is expected to affect the efficacy of degrading agents, but what extent it influences target not been systematically explored. Using mathematical modelling degradation, we demonstrate that natural dramatic effect on level induced by degrader agent which can pose significant hurdles screening efforts. Moreover, show upon for degraders short-lived proteins, agents stall synthesis,...
Despite the high prevalence of cancers driven by KRAS mutations, to date only G12C mutation has been clinically proven be druggable via covalent targeting mutated cysteine amino acid residue (1). However, in many cancer indications other such as G12D and -V, are far more prevalent small molecule concepts that can address a wider variety oncogenic alleles clinical demand (2). Here we show single used simultaneously potently degrade 13 out 17 most alleles, including those not yet tractable...
Retinoic acid (RA) has paradoxical effects on cancer cells: promoting cell death, differentiation and cycle arrest, or survival proliferation. Arachidonic (AA) release occurs in response to RA treatment and, therefore, AA its downstream metabolites may be involved signalling. To test this, we inhibited phospholipase A2-mediated release, cyclooxygenases lipoxygenases with small-molecule inhibitors determine if this would sensitise cells death after treatment. The data suggest that, RA, of...
Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit target E3 ligase, resulting in ubiquitylation proteosome-dependent target. The oral route administration is option choice clinic, but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed achieve orally bioavailable...
ABSTRACT Bifunctional degrader molecules, known as proteolysis-targeting chimeras (PROTACs), function by recruiting a target to an E3 ligase, forming target:PROTAC:ligase ternary complex. Despite the importance of this key intermediate species, no detailed validation method directly determine binding parameters for complex kinetics has been reported, and it remains be addressed whether tuning PROTAC complexes may effective strategy improve efficiency targeted protein degradation. Here, we...
Neurogenesis is a complex process leading to the generation of neuronal networks and glial cell types from stem cells or intermediate progenitors. Mapping subcellular molecular changes accompanying switch proliferation differentiation vital for developing therapeutic targets neurological diseases. Neuronal (N-type) (S-type) phenotypes within SH-SY5Y neuroblastoma line have distinct responses 9-cis-retinoic acid (9cRA). In both phenotypes, these were accompanied at single level by an...
Abstract Bivalent small-molecule degraders, or proteolysis targeting chimeras (PROTACs), work by simultaneously binding a target protein and E3 ubiquitin ligase to produce ternary complex. To drive ubiquitination degradation at low catalytic concentrations, degraders must form appropriately positioned complexes of sufficient stability, aided intra-complex interactions. We hypothesized these molecular recognition features could be enhanced increasing valency. Here we present trivalent PROTACs...
Introduction Proteolysis Targeting Chimaeras (PROTACs) offer a powerful strategy to degrade cancer-associated proteins. PROTACs recruit an E3 ubiquitin ligase, such as von Hippel-Lindau (VHL), protein of interest (POI) form ternary complex. Measuring the formation this species is important for understanding PROTAC mode action. Proximity AlphaLISA assays can be used purpose but have, date, focused on using purified recombinant in vitro . Here, we report development and optimisation assay...
Abstract Targeting subunits of BAF/PBAF complexes has been proposed as an approach to exploit cancer vulnerabilities, yet small molecules developed date have remained largely ineffectual. Here we develop PROTAC degraders the BAF ATPase SMARCA2 and SMARCA4 using a bromodomain ligand recruitment E3 ubiquitin ligase VHL. High-resolution ternary complex crystal structures biophysical investigation guided rational optimization ACBI1, potent cooperative SMARCA2/4 degrader. ACBI1 induced...