A5006466935- Protein Degradation and Inhibitors
- Histone Deacetylase Inhibitors Research
- Cytokine Signaling Pathways and Interactions
- Peptidase Inhibition and Analysis
- Chemical Synthesis and Analysis
- Click Chemistry and Applications
- Chronic Myeloid Leukemia Treatments
- Acute Myeloid Leukemia Research
- Chronic Lymphocytic Leukemia Research
- Tuberculosis Research and Epidemiology
- Immunodeficiency and Autoimmune Disorders
- Monoclonal and Polyclonal Antibodies Research
- Ubiquitin and proteasome pathways
- Computational Drug Discovery Methods
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Advanced Proteomics Techniques and Applications
- Glioma Diagnosis and Treatment
- Pancreatic and Hepatic Oncology Research
- Mass Spectrometry Techniques and Applications
- T-cell and Retrovirus Studies
- Cardiac Ischemia and Reperfusion
- Epigenetics and DNA Methylation
- Protein Tyrosine Phosphatases
- Crystallization and Solubility Studies
- Enzyme Structure and Function
University of Toronto
2016-2025
Medicina
2025
McMaster University
2023
Canadian Celiac Association
2017-2021
Physical Sciences (United States)
2015
The transcription factor STAT5 is an essential downstream mediator of many tyrosine kinases (TKs), particularly in hematopoietic cancers. activated by FLT3-ITD, which a constitutively active TK driving the pathogenesis acute myeloid leukemia (AML). Since critical diverse malignant properties AML cells, direct targeting significant clinical value. Here, we describe development and preclinical evaluation novel, potent SH2 domain inhibitor, AC-4-130, can efficiently block pathological levels...
Hyper-activated STAT5B variants are high value oncology targets for pharmacologic intervention. STAT5BN642H, a frequently-occurring oncogenic driver mutation, promotes aggressive T-cell leukemia/lymphoma in patient carriers, although the molecular origins remain unclear. Herein, we emphasize nature of STAT5BN642H driving neoplasia upon hematopoietic expression transgenic mice, revealing evidence multiple subset organ infiltration. Notably, demonstrate STAT5BN642H-driven transformation γδ...
Medulloblastoma (MB), the most common malignant paediatric brain tumor, is currently treated using a combination of surgery, craniospinal radiotherapy and chemotherapy. Owing to MB stem cells (MBSCs), subset patients remains untreatable despite standard therapy. CD133 used identify MBSCs although its functional role in tumorigenesis has yet be determined. In this work, we showed enrichment Group 3 associated with increased rate metastasis poor clinical outcome. The signal transducers...
Epigenetic targeting has emerged as an efficacious therapy for hematological cancers. The rare and incurable T-cell prolymphocytic leukemia (T-PLL) is known its aggressive clinical course. Current epigenetic agents such histone deacetylase (HDAC) inhibitors are increasingly used targeted therapy. Through a structure-activity relationship (SAR) study, we developed HDAC6 inhibitor KT-531, which exhibited higher potency in T-PLL compared to other KT-531 displayed strong inhibitory selectivity,...
Histone deacetylases (HDACs) are an attractive therapeutic target for a variety of human diseases. Currently, all four FDA-approved HDAC-targeting drugs nonselective, pan-HDAC inhibitors, exhibiting adverse side effects at doses. Although selective HDAC inhibition has been proposed to mitigate toxicity, the targeted catalytic domains highly conserved. Herein, we describe series rationally designed, conformationally constrained, benzanilide foldamers which selectively bind tunnel HDAC8. The...
Histone deacetylase 6 (HDAC6) has been targeted in clinical studies for anticancer effects due to its role oncogenic transformation and metastasis. Through a second-generation structure–activity relationship (SAR) study, the design, biological evaluation of selective HDAC6 inhibitor NN-390 is reported. With nanomolar potency, >200–550-fold selectivity analogous HDAC isoform functional assays, potent intracellular target engagement, robust cellular efficacy cancer cell lines, first...
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, incurable cancer with a 20% 1 year survival rate. While standard-of-care therapy can prolong life in small fraction of cases, PDAC inherently resistant to current treatments, and novel therapies are urgently required. Histone deacetylase (HDAC) inhibitors effective killing pancreatic cells vitro studies, although there few clinical studies investigating combination including HDAC inhibitors, no drug or has been approved for the...
Thyroid hormone (TH) signaling plays a major role in the development, energy homeostasis, and metabolism of most tissues. Recent observations have identified THs as drivers prostate cancer (PCa) tumor development progression. We reported that T3-scavenger protein μ-crystallin (CRYM) regulates progression PCa this involved crosstalk with androgen receptor (AR) signaling. However, mechanisms remain incompletely understood. Here, we explored thyroid β (TRβ), which is main effector TH signaling,...
A rapid and efficient microwave-assisted synthesis of pomalidomide analogs, improving upon prior methods to accelerate the discovery optimization degraders like clinical candidate ARV-110.
Herein, we report a potent HDAC6 PROTAC, TO-1187, which selectively degrades in cellulo and demonstrates vivo efficacy. The design of TO-1187 was achieved by linking our previously reported inhibitor, TO-317, to the cereblon (CRBN) E3 ligase ligand, pomalidomide. monoselective degradation human multiple myeloma cells, MM.1S, with Dmax 94% DC50 5.81 nM after 6 h. Importantly, at concentrations up 25 μM, exhibited no cellular other HDACs. Proteomic evaluation confirmed highly selective...
Abstract Pharmacologic blockade of the activation signal transducer and activator transcription 3 (STAT3) in tyrosine kinase inhibitor (TKI)‐resistant chronic myeloid leukemia (CML) cell lines characterized by kinase‐independent resistance was shown to re‐sensitize CML cells TKI therapy, suggesting that STAT3 inhibitors combination with TKIs are an effective combinatorial therapeutic for treatment CML. Benzoic acid‐ hydroxamic acid‐based SH‐4‐054 SH‐5‐007, developed previously our...
Antibiotic resistance is a major problem for world health, triggered by the unnecessary usage of broad-spectrum antibiotics on purportedly infected patients. Current clinical standards require lengthy protocols detection bacterial species in sterile physiological fluids. In this work, class small-molecule fluorescent chemosensors termed ProxyPhos was shown to be capable rapid, sensitive, and facile bacteria. The sensors act via turn-on excimer mechanism, where close-proximity binding...
Histone deacetylase 6 (HDAC6) is involved in multiple regulatory processes, ranging from cellular stress to intracellular transport. Inhibition of aberrant HDAC6 activity several cancers and neurological diseases has been shown be efficacious both preclinical clinical studies. While selective targeting pursued as an alternative pan-HDAC drugs, identifying truly molecular templates not trivial. Herein, we report a structure-activity relationship study yielding
Histone deacetylases (HDACs) have emerged as powerful epigenetic modifiers of histone/non-histone proteins via catalyzing the deacetylation ε-N-acetyl lysines. The dysregulated activity these Zn2+-dependent hydrolases has been broadly implicated in disease, notably cancer. Clinically, recurring dose-limiting toxicities first-generation HDACi sparked a paradigm shift toward safer isoform-specific molecules. With pervasive roles aggressive diseases, there remains need for novel approaches to...
The HDAC inhibitor 4-tert-butyl-N-(4-(hydroxycarbamoyl)phenyl)benzamide (AES-350, 51) was identified as a promising preclinical candidate for the treatment of acute myeloid leukemia (AML), an aggressive malignancy with meagre 24% 5-year survival rate. Through screening low-molecular-weight analogues derived from previously discovered novel inhibitor, AES-135, compound 51 demonstrated greater isoform selectivity, higher cytotoxicity in MV4-11 cells, improved therapeutic window, and more...
Janus kinase 2 (JAK2) and signal transducer activator of transcription-5 (STAT5) play a key role in the pathogenesis myeloproliferative neoplasms (MPN). In most patients, JAK2 V617F or CALR mutations are found lead to activation various downstream signaling cascades molecules, including STAT5. We examined presence distribution phosphorylated (p) STAT5 neoplastic cells patients with MPN, polycythemia vera (PV, n = 10), essential thrombocythemia (ET, 15) primary myelofibrosis (PMF, 9),...