A5082451886- Cancer-related gene regulation
- Epigenetics and DNA Methylation
- Enzyme Structure and Function
- Organoboron and organosilicon chemistry
- Neurological diseases and metabolism
- RNA modifications and cancer
- Chemical Synthesis and Analysis
- Radical Photochemical Reactions
- Crystallization and Solubility Studies
- Chemical Synthesis and Reactions
- RNA and protein synthesis mechanisms
- Asymmetric Synthesis and Catalysis
- Crystallography and molecular interactions
- X-ray Diffraction in Crystallography
- Viral Infectious Diseases and Gene Expression in Insects
- Histone Deacetylase Inhibitors Research
- Glioma Diagnosis and Treatment
- Catalytic C–H Functionalization Methods
- 14-3-3 protein interactions
- TGF-β signaling in diseases
- Synthetic Organic Chemistry Methods
- Microtubule and mitosis dynamics
- Cancer Treatment and Pharmacology
- Acute Myeloid Leukemia Research
- Peptidase Inhibition and Analysis
Ontario Institute for Cancer Research
2015-2024
Structural Genomics Consortium
2012-2021
University of Toronto
2012-2021
Toronto Public Health
2016
Princess Margaret Cancer Centre
2015
University Health Network
2015
Ottawa University
2004-2005
University of Ottawa
2003
WDR5 (WD40 repeat protein 5) is an essential component of the human trithorax-like family SET1 [Su(var)3-9 enhancer-of-zeste trithorax 1] methyltransferase complexes that carry out trimethylation histone 3 Lys4 (H3K4me3), play key roles in development and are abnormally expressed many cancers. In present study, we show interaction between peptides from catalytic domain MLL (mixed-lineage leukaemia protein) (KMT2) can be antagonized with a small molecule. Structural biophysical analysis this...
Protein methyltransferases (PMTs) comprise a major class of epigenetic regulatory enzymes with therapeutic relevance. Here we present collection chemical probes and associated reagents data to elucidate the function human murine PMTs in cellular studies. Our provides inhibitors antagonists that together modulate most key methylation marks on histones H3 H4, providing an important resource for modulating epigenomes. We describe comprehensive comparative characterization probe respect their...
Abstract PRMT3 catalyzes the asymmetric dimethylation of arginine residues various proteins. It is essential for maturation ribosomes, may have a role in lipogenesis, and implicated several diseases. A potent, selective, cell‐active inhibitor would be valuable tool further investigating biology. Here we report discovery first chemical probe, SGC707, by structure‐based optimization allosteric inhibitors reported previously, thorough characterization this probe biochemical, biophysical,...
The COVID-19 pandemic has clearly brought the healthcare systems worldwide to a breaking point, along with devastating socioeconomic consequences. SARS-CoV-2 virus, which causes disease, uses RNA capping evade human immune system. Nonstructural protein (nsp) 14 is one of 16 nsps in and catalyzes methylation viral at N7-guanosine cap formation process. To discover small-molecule inhibitors nsp14 methyltransferase (MTase) activity, we developed employed radiometric MTase assay screen library...
Potassium alkenyl- and aryltrifluoroborates undergo addition to enones aldehydes in the presence of Rh(I) catalysts give β-functionalized ketones allylic/benzylic alcohols, respectively. Reaction proceeds more rapidly than with corresponding boronic acids, choice phosphine ligand does not signifcantly influence overall efficiency addition.
The protein arginine methyltransferases PRMT7 and PRMT5, respectively, monomethylate symmetrically dimethylate side-chains of proteins involved in diverse cellular mechanisms, including chromatin-mediated control gene transcription, splicing, the RAS to ERK transduction cascade. It is believed that PRMT5 act conjunction methylate their substrates, genetic deletions support notion these enzymes derepress cell proliferation migration cancer. Using available structures we designed DS-437, a...
WD repeat-containing protein 5 (WDR5) is an important component of the multiprotein complex essential for activating mixed-lineage leukemia 1 (MLL1). Rearrangement MLL1 gene associated with onset and progression acute myeloid lymphoblastic leukemias, targeting WDR5-MLL1 interaction may result in new cancer therapeutics. Our previous work showed that binding small molecule ligands to WDR5 can modulate its MLL1, suppressing methyltransferase activity. Initial structure–activity relationship...
Well-characterized selective inhibitors of protein arginine methyltransferases (PRMTs) are invaluable chemical tools for testing biological and therapeutic hypotheses. Based on 4, a fragment-like inhibitor type I PRMTs, we conducted structure–activity relationship (SAR) studies explored three regions this scaffold. The led to the discovery potent, selective, cell-active dual PRMT4 PRMT6, 17 (MS049). As compared displayed much improved potency PRMT6 in both biochemical cellular assays. It was...
Potassium allyl- and crotyltrifluoroborates react with aldehydes in a process catalyzed by variety of Lewis acids, to give the corresponding homoallylic alcohols. Of acids examined, BF3 · OEt2, used either stoichiometrically or catalytically, was found most efficiently catalyze this reaction. The air moisture stable potassium organotrifluoroborate salts alkyl, α- β-substituted aryl aldehydes, lead adducts high yield diastereoselectivity.
Protein arginine methyltransferases (PRMTs) play an important role in diverse biological processes. Among the nine known human PRMTs, PRMT3 has been implicated ribosomal biosynthesis via asymmetric dimethylation of 40S protein S2 and cancer interaction with DAL-1 tumor suppressor protein. However, few selective inhibitors PRMTs have discovered. We recently disclosed first inhibitor, which occupies a novel allosteric binding site is noncompetitive both peptide substrate cofactor. Here we...
The WD40-repeat protein WDR5 plays a critical role in maintaining the integrity of MLL complexes and fully activating their methyltransferase function. complexes, trithorax-like family SET1 methyltransferases, catalyze trimethylation lysine 4 on histone 3, they have been widely implicated various cancers. Antagonism subunit interaction by small molecules has recently presented as practical way to inhibit activity MLL1 complex, N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides...
Protein arginine methyltransferases (PRMTs) represent an emerging target class in oncology and other disease areas. So far, the most successful strategy to identify PRMT inhibitors has been screen large medium-size chemical libraries. Attempts develop using receptor-based computational methods have met limited success. Here, virtual screening approaches, we 11 CARM1 (PRMT4) with ligand efficiencies ranging from 0.28 0.84. selective hits were further validated by orthogonal methods. Two...
Post-translational modification of bacterial elongation factor P (EF-P) with (R)-β-lysine at a conserved lysine residue activates the protein in vivo and increases puromycin reactivity ribosome vitro. The additional hydroxylation EF-P same by YfcM has also recently been described. roles modified unmodified during different steps translation, how this correlates to its physiological role cell, have linked synthesis polyproline stretches proteins. Polysome analysis indicated that functions...
5-, 6-, and even 7-exo-trig radical cyclizations (1→2) are possible by applying a new boron-tethering approach with alkenylboronic esters. For certain substitution patterns, subsequent intramolecular homolytic (SH i) reaction at boron occurs (2→3) leads to rearranged products. The C-B bond of the intermediate boracycles is readily oxidized give diol
Cytochrome P450scc (CYP 11A1) catalyzes the conversion of cholesterol (Ch) to pregnenolone, precursor steroid hormones. This process proceeds via three sequential monooxygenation reactions: two hydroxylations Ch first form 22(R)-hydroxycholesterol (HC) and then 20α,22(R)-dihydroxycholesterol (DHC); a lyase reaction cleaves C20–C22 bond pregnenolone. Recent cryoreduction/annealing studies that employed electron paramagnetic resonance (EPR)/electron nuclear double (ENDOR) spectroscopy...
Protein methyltransferases (PMTs) are a promising target class in oncology and other disease areas. They composed of SET domain structurally unrelated Rossman-fold enzymes that include protein arginine (PRMTs). In the absence well-defined medicinal chemistry tool-kit focused on PMTs, most current inhibitors were identified by screening large diverse libraries leadlike molecules. So far, no successful fragment-based approach was reported against this class. Here, deconstructing potent PRMT...