A5048502984- Protein Degradation and Inhibitors
- X-ray Diffraction in Crystallography
- Multiple Myeloma Research and Treatments
- Crystallization and Solubility Studies
- Ubiquitin and proteasome pathways
- CAR-T cell therapy research
- Histone Deacetylase Inhibitors Research
- Immunotherapy and Immune Responses
- Immune Cell Function and Interaction
- Radical Photochemical Reactions
- Peptidase Inhibition and Analysis
- Organic Chemistry Cycloaddition Reactions
- Biochemical effects in animals
- Connexins and lens biology
- Photochromic and Fluorescence Chemistry
- Oxidative Organic Chemistry Reactions
- biodegradable polymer synthesis and properties
- RNA Interference and Gene Delivery
- Surgical Sutures and Adhesives
- Software Testing and Debugging Techniques
- Neuroscience of respiration and sleep
- Porphyrin and Phthalocyanine Chemistry
- Orthopaedic implants and arthroplasty
Novartis (United States)
2024
University of Calgary
2016-2024
Innovative Genomics Institute
2022-2023
University of California, Berkeley
2022-2023
Novartis (Ireland)
2022
Calgary Laboratory Services
2016
Northwest University
2016
Targeted protein degradation with molecular glue degraders has arisen as a powerful therapeutic modality for eliminating classically undruggable disease-causing proteins through proteasome-mediated degradation. However, we currently lack rational chemical design principles converting protein-targeting ligands into degraders. To overcome this challenge, sought to identify transposable handle that would convert of their corresponding targets. Using the CDK4/6 inhibitor ribociclib prototype,...
Targeted protein degradation with monovalent molecular glue degraders is a powerful therapeutic modality for eliminating disease causing proteins. However, rational design of remains challenging. In this study, we sought to identify transplantable and linker-less covalent handle that could be appended onto the exit vector various protein-targeting ligands induce their respective targets. Using BET family inhibitor JQ1 as testbed, synthesized screened series analogs identified vinylsulfonyl...
Protein–protein interactions (PPIs) have emerged as significant targets for therapeutic development, owing to their critical nature in diverse biological processes. An ideal PPI-based target is the protein myeloid cell leukemia 1 (MCL1), a prosurvival factor cancers such multiple myeloma where MCL1 levels directly correlate disease progression. Current strategies halting antiapoptotic properties of revolve around inhibiting its sequestration proapoptotic factors. Existing inhibitors disrupt...
Thiophene-containing porphyrin compounds are capable of catalytic, photo-reductive dehalogenation on an array α-halo ketone model substrates with low catalyst loadings (0.1 mol%), in the presence energy, red light (>645 nm).
Abstract Opioid withdrawal is a liability of chronic opioid use and misuse, impacting people who prescription or illicit opioids. Hyperactive autonomic output underlies many the aversive symptoms that make it difficult to discontinue use. The locus coeruleus (LC) an important centre within brain with poorly defined role in withdrawal. We show here pannexin-1 (Panx1) channels expressed on microglia critically modulate LC activity during Within LC, we found spinally projecting tyrosine...
Gamma delta T cells (γδTc) have tremendous anti-tumoral activity, thus γδTc immunotherapy is currently under development for various malignancies. We targeted breast cancer stem-like (BCSC), a rare cell population responsible patient mortality. BCSC were mostly susceptible to immunotherapy, yet some escaped. The secretome rendered hypo-responsive, and resistant expressed more PD-L1 anti-apoptotic protein MCL-1 than non-stem-like (NSC). resistance was partially overcome by dMCL1-2, an...
Abstract Targeted protein degradation with monovalent molecular glue degraders is a powerful therapeutic modality for eliminating disease causing proteins. However, rational design of remains challenging. In this study, we sought to identify transplantable and linker-less covalent handle that could be appended onto the exit vector various protein-targeting ligands induce their respective targets. Using BET family inhibitor JQ1 as testbed, synthesized screened series analogs identified...
The synthesis of small-molecule linkers for installation thalidomide-based conjugates is described. Linker properties have been recognized as vital to conjugate success in drug discovery and delivery systems. These tethers act linkages between molecules, can also aid cell permeability, solubilizing agents. This work shows our progress synthesizing with a variety linker characteristics. adaptability manipulation these other holds potential improving synthetic control chemical connectivities...
To develop new degrader molecules from an existing protein ligand a linkage vector must be identified and then joined with suitable E3 ligase without disrupting binding to the respective targets. This is typically achieved through empirically evaluating degradation efficacy of series synthetic degraders. Our strategy for determining optimal sites utilises biotinylated ligands, linked via potential conjugation inhibitor confirm whether target maintained after forming conjugate. method...
The reactions of bicyclic divinyl ketones display wavelength-dependent changes in product formation. UV irradiation results the formation competitive [6,3,5] and [7,3,5] tricyclic unsaturated that subsequently undergo ring expansion reaction with a range nucleophiles. DFT calculations transient absorption experiments were completed are consistent vinylogous Type II Norrish pathway.
Abstract Targeted protein degradation with molecular glue degraders has arisen as a powerful therapeutic modality for eliminating classically undruggable disease-causing proteins through proteasome-mediated degradation. However, we currently lack rational chemical design principles converting protein-targeting ligands into degraders. To overcome this challenge, sought to identify transposable handle that would convert of their corresponding targets. Using the CDK4/6 inhibitor Ribociclib...
Abstract Breast cancer stem cells (BCSC) are highly resistant to current therapies, and responsible for metastatic burden relapse. Gamma delta T (γδTc) immunosurveillance with tremendous anti-tumoral activity, a growing number of clinical trials have confirmed the safety γδTc immunotherapy various malignancies. Herein, we demonstrate that can kill BCSC, but lesser extent than non-cancer (NSC). Immune evasion was orchestrated by several mechanisms. The BCSC secretome rendered hypo-responsive...
Here we show the development of heterobifunctional small molecules capable selectively targeting MCL1 using a Proteolysis Targeting Chimera (PROTAC) methodology leading to successful degradation. We have confirmed involvement E3 ligase CUL4A-DDB1 cereblon (CRBN) ubiquitination pathway, making these PROTACs first step toward new class anti-apoptotic BCL-2 family protein degraders.
<div> <p>Here we show the development of heterobifunctional small molecules capable selectively targeting MCL1 using a Proteolysis Targeting Chimera (PROTAC) methodology leading to successful degradation. We have confirmed involvement E3 ligase CUL4A-DDB1 cereblon (CRBN) ubiquitination pathway, making these PROTACs first step toward new class anti-apoptotic BCL-2 family protein degraders. </p> </div>