A5101818961- Cancer therapeutics and mechanisms
- DNA and Nucleic Acid Chemistry
- Tuberculosis Research and Epidemiology
- Phagocytosis and Immune Regulation
- Cancer Genomics and Diagnostics
- Folate and B Vitamins Research
- DNA Repair Mechanisms
- Immune cells in cancer
- Peptidase Inhibition and Analysis
- Mycobacterium research and diagnosis
- Pancreatic and Hepatic Oncology Research
- Advanced Breast Cancer Therapies
- Porphyrin Metabolism and Disorders
- Dementia and Cognitive Impairment Research
- Chemical Synthesis and Analysis
- Cancer-related Molecular Pathways
- RNA modifications and cancer
- Advanced biosensing and bioanalysis techniques
- Acute Myeloid Leukemia Research
- Chronic Myeloid Leukemia Treatments
- Acute Lymphoblastic Leukemia research
- Pneumocystis jirovecii pneumonia detection and treatment
- Metal complexes synthesis and properties
- HIV/AIDS drug development and treatment
- Sirtuins and Resveratrol in Medicine
Brigham and Women's Hospital
2025
Harvard University
2025
Qurient (South Korea)
2018-2024
Princess Margaret Cancer Centre
2018-2023
University Health Network
2018-2023
Asan Medical Center
2016-2023
University of Toronto
2016-2021
Ontario Institute for Cancer Research
2016-2020
Institut Pasteur Korea
2009-2020
McGill University
2010-2014
A critical feature of Mycobacterium tuberculosis, the causative agent human tuberculosis (TB), is its ability to survive and multiply within macrophages, making these host cells an ideal niche for persisting microbes. Killing intracellular tubercle bacilli a key requirement efficient treatment, yet identifying potent inhibitors has been hampered by labor-intensive techniques lack validated targets. Here, we present development phenotypic cell-based assay that uses automated confocal...
A critical unmet clinical need to combat the global tuberculosis epidemic is development of potent agents capable reducing time multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) therapy. In this paper, we report on optimization imidazo[1,2-a]pyridine amide (IPA) lead compound 1, which led design synthesis Q203 (50). We found that linker with IPA core very important for activity against Mycobacterium H37Rv. Linearity lipophilicity amine part in series play a role improving vitro...
Abstract In BCR-ABL1 lymphoblastic leukemia, treatment heterogeneity to tyrosine kinase inhibitors (TKIs), especially in the absence of domain mutations , is poorly understood. Through deep molecular profiling, we uncovered three transcriptomic subtypes each representing a maturation arrest at stage B-cell progenitor differentiation. An earlier was associated with lineage promiscuity, refractoriness and poor patient outcomes. A later fidelity, durable leukemia remissions improved Each marked...
The repertoire of currently available antiviral drugs spans therapeutic applications against a number important human pathogens distributed worldwide. These include cases the pandemic severe acute respiratory coronavirus type 2 (SARS-CoV-2 or COVID-19), immunodeficiency virus 1 (HIV-1 AIDS), and pregnancy- posttransplant-relevant cytomegalovirus (HCMV). In almost all cases, approved therapies are based on direct-acting antivirals (DAAs), but their benefit, particularly in long-term...
Tuberculosis is still a leading cause of death worldwide. The selection and spread Mycobacterium tuberculosis multidrug-resistant (MDR-TB) extensively drug-resistant strains (XDR-TB) severe public health problem. Recently, two different classes chemical series, the benzothiazinones (BTZ) dinitrobenzamide (DNB) derivatives have been found to be highly active against M. tuberculosis, including XDR-TB strains. target BTZs DprE1 protein which works in concert with DprE2 form heteromeric...
Telacebec (Q203) is a potent drug candidate under clinical development for the treatment of drug-naïve and drug-resistant tuberculosis. The first-in-human randomized, placebo-controlled, double-blind, dose-escalation Phase 1A trial (Q203-TB-PI-US001) was conducted to evaluate safety, tolerability, pharmacokinetics telacebec. A total 56 normal, healthy, male female subjects (42 active 14 placebo) were enrolled in study. doses telacebec 10 mg (Cohort 1), 30 2), 50 3), 100 4), 200 5), 400 6),...
Four stereoisomers of a Phe-Ala silanediol dipeptide mimic have been evaluated as inhibitors angiotensin-converting enzyme (ACE) and compared to ketone-based reported by Almquist et al. One stereogenic center the isomers was derived from individual enantiomers methyl 3-hydroxy-2-methylpropionate, with separation diastereomers after introduction second center. The diastereomeric identities were established X-ray crystallography an intermediate. Inhibition ACE three (IC(50) = 3.8-207 nM)...
Mutations in human LMBRD1 and ABCD4 prevent lysosomal export of vitamin B12 to the cytoplasm, impairing B12-dependent enzymes methionine synthase methylmalonyl-CoA mutase. The gene products are implicated transport at membrane proposed act complex. To address mechanism for transport, we report novel recombinant production LMBD1 detailed biophysical analyses. Using blue native PAGE, chemical crosslinking, size exclusion chromatography coupled multi-angle light scattering (SEC-MALS), show that...
Dialkylsilanediols have been found to be an effective functional group for the design of active-site-directed protease inhibitors, including aspartic (HIV protease) and metallo (ACE thermolysin) proteases. The use silanediols is predicated on its resemblance hydrated carbonyl transition-state structure amide hydrolysis. This concept has tested by replacing presumed tetrahedral carbon a thermolysin substrate with silanediol group, resulting in inhibitor inhibition constant Ki = 40 nM. bound...
A silanediol inhibitor of the metalloprotease thermolysin was prepared for comparison to a known phosphinic acid inhibitor, providing first these second-row element based transition-state analogues. Inhibition by (Ki = 41 nM) comparable that 10 even though is uncharged and thereby lacks intrinsic Coulombic attraction phosphinate anion active-site zinc cation. This protease least sterically encumbered example date and, therefore, most prone toward polymerization. Hydrolysis difluorosilane...
2-Deoxyribonolactone (L) and the C4'-oxidized abasic site (C4-AP) are produced by a variety of DNA-damaging agents. If not repaired, these lesions can be mutagenic. Exonuclease III endonuclease IV major enzymes in E. coli responsible for 5'-incision sites (APs), first steps AP repair. Endonuclease efficiently excises via intermediate Schiff-base formation. Incision L C4-AP exonuclease was determined under steady-state conditions using oligonucleotide duplexes containing at defined sites. An...