A5036624979- Protein Degradation and Inhibitors
- Click Chemistry and Applications
- Ubiquitin and proteasome pathways
- Cancer therapeutics and mechanisms
- HER2/EGFR in Cancer Research
- Melanoma and MAPK Pathways
- Asymmetric Synthesis and Catalysis
- Receptor Mechanisms and Signaling
- Glioma Diagnosis and Treatment
- Synthesis and biological activity
- Cancer-related Molecular Pathways
- Synthetic Organic Chemistry Methods
- Peptidase Inhibition and Analysis
- Computational Drug Discovery Methods
- Endoplasmic Reticulum Stress and Disease
- Chronic Lymphocytic Leukemia Research
- Lung Cancer Treatments and Mutations
- Cell death mechanisms and regulation
- Neuroblastoma Research and Treatments
- Signaling Pathways in Disease
- Multiple Myeloma Research and Treatments
- Chemical Synthesis and Analysis
- Chemical synthesis and alkaloids
- TGF-β signaling in diseases
- Synthesis and Biological Evaluation
University of Toronto
2011-2024
Ontario Institute for Cancer Research
2014-2024
American Association For Cancer Research
2023
University Health Network
2014
Hospital for Sick Children
2011-2014
GlaxoSmithKline (United States)
2001-2013
Research Triangle Park Foundation
2000-2013
Lunenfeld-Tanenbaum Research Institute
2011
University of Perugia
2011
Molecular Oncology (United States)
2008
Hyperactive signaling of the MAP kinase pathway resulting from constitutively active B-Raf(V600E) mutated enzyme has been observed in a number human tumors, including melanomas. Herein we report discovery and biological evaluation GSK2118436, selective inhibitor Raf kinases with potent vitro activity oncogenic B-Raf-driven melanoma colorectal carcinoma cells robust vivo antitumor pharmacodynamic mouse models melanoma. GSK2118436 was identified as development candidate, early clinical results...
Glioblastoma is one of the most lethal cancers in humans, and with existing therapy, survival remains at 14.6 months. Current barriers to successful treatment include their infiltrative behavior, extensive tumor heterogeneity, presence a stem-like population cells, termed brain tumor-initiating cells (BTIC) that confer resistance conventional therapies.To develop therapeutic strategies target BTICs, we focused on repurposing approach explored already-marketed (clinically approved) drugs for...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTotal synthesis of FK506 and an FKBP probe reagent, [C(8),C(9)-13C2]-FK506Masashi Nakatsuka, John A. Ragan, Tarek Sammakia, David B. Smith, E. Uehling, Stuart L. SchreiberCite this: J. Am. Chem. Soc. 1990, 112, 14, 5583–5601Publication Date (Print):July 1, 1990Publication History Published online1 May 2002Published inissue 1 July 1990https://pubs.acs.org/doi/10.1021/ja00170a024https://doi.org/10.1021/ja00170a024research-articleACS...
Mitogen-Activated Protein Kinase (MAPK) pathway activation has been implicated in many types of human cancer. BRAF mutations that constitutively activate MAPK signalling and bypass the need for upstream stimuli occur with high prevalence melanoma, colorectal carcinoma, ovarian cancer, papillary thyroid cholangiocarcinoma. In this report we characterize novel, potent, selective inhibitor, dabrafenib (GSK2118436). Cellular inhibition BRAF(V600E) kinase activity by resulted decreased MEK ERK...
The synthesis and antitumor activities of the novel water soluble camptothecin derivatives 7-[(4-methylpiperazino)methyl]-10,11-(methylenedioxy)-(20S)-campto thecin trifluoroacetate (6) 7-[(4-methylpiperazino)methyl]-10,11-(ethylenedioxy)-(20S)-camptot hecin (7) are described. solubilities compounds 6 7 were measured to be 4.5 5.8 mg/mL, respectively, in pH 5 acetate buffer contrast < 0.003 mg/mL for same buffer. In purified topoisomerase I cleavable complex enzyme assay, demonstrated potent...
Analysis of the x-ray crystal structure mono-substituted acetylenic thienopyrimidine 6 complexed with ErbB family enzyme ErbB-4 revealed a covalent bond between terminal carbon acetylene moiety and sulfhydryl group Cys-803 at solvent interface. The identification this adduct suggested that related analogs might also be capable forming an analogous EGFR, which has conserved cysteine (797) near ATP binding pocket. To test hypothesis, we treated truncated, catalytically competent form EGFR...
Neuroblastoma (NB) is an often fatal pediatric tumor of neural crest origin. We previously isolated NB tumor-initiating cells (NB TIC) from bone marrow metastases that resemble cancer stem and form metastatic in immunodeficient animals with as few ten cells. To identify signaling pathways important for the survival self-renewal TICs potential therapeutic targets, we screened a small molecule library 143 protein kinase inhibitors, including 33 clinical trials. Cytostatic or cytotoxic drugs...
Muscle fiber formation from progenitor cells is dependent on noncanonical NF-κB signaling.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAcyclic stereoselection. 29. Stereoselection in the Michael addition reaction. 1. The Mukaiyama-Michael reactionClayton H. Heathcock, Mark Norman, and David E. UehlingCite this: J. Am. Chem. Soc. 1985, 107, 9, 2797–2799Publication Date (Print):May 1, 1985Publication History Published online1 May 2002Published inissue 1 1985https://doi.org/10.1021/ja00295a037RIGHTS & PERMISSIONSArticle Views986Altmetric-Citations89LEARN ABOUT THESE METRICSArticle...
Leiomyosarcoma (LMS) is a common type of soft tissue sarcoma that responds poorly to standard chemotherapy. Thus the goal this study was identify novel selective therapies may be effective in leiomyosarcoma by screening cell lines with small molecule library comprised 480 kinase inhibitors functionally determine which signalling pathways critical for LMS growth.
// Natalie Grinshtein 1 , Constanza C. Rioseco Richard Marcellus 2 David Uehling Ahmed Aman Xueqing Lun 3 Osamu Muto Lauren Podmore Jake Lever 4 Yaoqing Shen Michael D. Blough Greg J. Cairncross Stephen M. Robbins Steven Jones 4, 5, 6 Marco A. Marra 5 Rima Al-Awar Donna L. Senger R. Kaplan 1, 7 Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada Drug Discovery Group, Ontario Institute Cancer Research, ON, Arnie Charbonneau Institute, Department of...
Metabolic diseases are increasing at staggering rates globally. The peroxisome proliferator-activated receptors (PPARα/γ/δ) fatty acid sensors that help mitigate imbalances between energy uptake and utilization. Herein, we report compounds derived from phenolic lipids present in cashew nut shell liquid (CNSL), an abundant waste byproduct, effort to create effective, accessible, sustainable drugs. Derivatives of anacardic cardanol were tested for PPAR activity HEK293 cell co-transfection...
ADVERTISEMENT RETURN TO ISSUEPREVArticleAcyclic stereoselection. Part 34. Stereoselection in the Michael addition reaction. 4. Diastereofacial preferences Lewis acid-mediated additions of enolsilanes to chiral enonesClayton H. Heathcock and David E. UehlingCite this: J. Org. Chem. 1986, 51, 2, 279–280Publication Date (Print):January 1, 1986Publication History Published online1 May 2002Published inissue 1 January...
Abstract Activation of the Ras-Raf-MEK-ERK pathway has been implicated in a large range human cancers. Growth factor receptor stimulation by extracellular ligands activates Ras, which then sets motion signal transduction cascade through Raf, MEK and ERK serine/threonine kinases. Mutation B-Raf kinase constitutively MAPK signalling, thus bypassing need for upstream stimuli. This genetically associated with several cancers, especially occurrence B-RafV600E mutant its high prevalence melanoma,...
The pro-apoptotic protein Bax commits a cell to death by permeabilizing the mitochondrial outer membrane (MOM). To obtain small-molecule probes for elucidating molecular mechanism(s) of activation, we screened compounds that induced Bax-mediated liposome permeabilization. We identified five structurally different small molecules promoted both targeting and oligomerization at membranes. All initiated in absence membranes mechanism unlike activation Bcl-2 homology 3 domain (BH3) proteins. Some...
Starting from phenethanolamine aniline leads 3a and 3b, we have identified a series of functionally potent selective beta(3) adrenergic receptor (AR) agonists containing acylsulfonamide, sulfonylsulfonamide, or sulfonylurea groups within the series. In beta(3), beta(2), beta(1) AR cAMP functional assays, other right-hand side (RHS) carboxylate analogues were found to be full that modestly against beta(2) ARs, while lacking RHS acid functionality active at but not selective. Replacement with...