A5086899217- Acute Lymphoblastic Leukemia research
- Protein Degradation and Inhibitors
- Acute Myeloid Leukemia Research
- Lymphoma Diagnosis and Treatment
- SARS-CoV-2 and COVID-19 Research
- CAR-T cell therapy research
- Ubiquitin and proteasome pathways
- Chronic Lymphocytic Leukemia Research
- Eosinophilic Disorders and Syndromes
- Histone Deacetylase Inhibitors Research
- Peptidase Inhibition and Analysis
- Influenza Virus Research Studies
- Biochemical and Molecular Research
- Retinoids in leukemia and cellular processes
- Multiple Myeloma Research and Treatments
- SARS-CoV-2 detection and testing
- Cervical Cancer and HPV Research
- Vaccine Coverage and Hesitancy
- Clinical Laboratory Practices and Quality Control
- Immunotherapy and Immune Responses
- Endoplasmic Reticulum Stress and Disease
- Adenosine and Purinergic Signaling
- COVID-19 Clinical Research Studies
- Chronic Myeloid Leukemia Treatments
- RNA modifications and cancer
Harvard University
2020-2024
Dana-Farber Cancer Institute
2021-2024
Broad Institute
2020-2024
Harvard University Press
2022
Johns Hopkins University
2020
National Taiwan University
2014
Abstract Small molecules that induce protein-protein interactions to exert proximity-driven pharmacology such as targeted protein degradation are a powerful class of therapeutics 1-3 . Molecular glues particular interest given their favorable size and chemical properties represent the only clinically approved degrader drugs 4-6 The discovery development molecular for novel targets, however, remains challenging. Covalent strategies could in principle facilitate glue by stabilizing neo-protein...
Nuclear hormone receptors (NRs) are ligand-binding transcription factors that widely targeted therapeutically. Agonist binding triggers NR activation and subsequent degradation by unknown ligand-dependent ubiquitin ligase machinery. is critical for therapeutic efficacy in malignancies driven retinoic acid estrogen receptors. Here, we demonstrate the UBR5 drives of multiple agonist-bound NRs, including receptor alpha (RARA), retinoid x (RXRA), glucocorticoid, estrogen, liver-X, progesterone,...
Targeted protein degradation relies on small molecules that induce new protein-protein interactions between targets and the cellular machinery. Most of these feature specific ligands for ubiquitin ligases. Recently, attachment cysteine-reactive chemical groups to pre-existing molecule inhibitors has been shown drive target degradation. We demonstrate here different can specify via distinct By focusing bromodomain ligand JQ1, we identify functional BRD4 by either DCAF16 or DCAF11. Unlike...
Abstract Molecular glues are proximity-inducing small molecules that have emerged as an attractive therapeutic approach. However, developing molecular remains challenging, requiring innovative mechanistic strategies to stabilize neoprotein interfaces and expedite discovery. Here we unveil a trans -labeling covalent glue mechanism, termed ‘template-assisted modification’. We identified new series of BRD4 degraders recruit CUL4 DCAF16 ligase the second bromodomain (BRD4 BD2 ). Through...
Immunomodulatory drugs are a class of approved for the treatment multiple myeloma. These compounds exert their clinical effects by inducing interactions between CRL4
Small molecules that can induce protein degradation by inducing proximity between a desired target and an E3 ligase have the potential to greatly expand number of proteins be manipulated pharmacologically. Current strategies for targeted are mostly limited in their scope with preexisting ligands. Alternate modalities such as molecular glues, exemplified glutarimide class ligands CUL4
The COVID-19 pandemic has made a devastating impact on global health and continues to challenge healthcare infrastructure delivery. clinical laboratories were no exception as they are responsible for diagnostic testing that dictates many clinical, infection control, public decisions. Information technology laboratory management tools critical assets maintaining adapting operations in response crises. When utilized effectively, promote the integration between specialties (e.g., chemistry,...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hijacks multiple human proteins during infection and viral replication. To examine whether any employ E3 ubiquitin ligases, we evaluated the stability of SARS-CoV-2 with inhibition proteasome pathway. Using genetic screens to dissect molecular machinery involved in degradation candidate proteins, identified ligase RNF185 as a regulator protein for envelope protein. We found that co-localize endoplasmic reticulum (ER). Finally,...
There is an urgent need for rapid methods to develop vaccines in response emerging viral pathogens.Whole inactivated virus (WIV) represent ideal strategy this purpose; however, a universal method producing safe and immunogenic lacking.Conventional pathogen inactivation such as formalin, heat, ultraviolet light, gamma rays cause structural alterations that lead reduced neutralizing antibody specificity, some cases, disastrous T helper type 2-mediated immune pathology.We have evaluated the...
Abstract Purpose: Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) lymphoma (T-LBL) have limited therapeutic options. Clinical use of genomic profiling provides an opportunity to identify targetable alterations inform therapy. Experimental Design: We describe a cohort 14 pediatric patients T-ALL enrolled on the Leukemia Precision-based Therapy (LEAP) Consortium trial (NCT02670525) and patient T-LBL, discovering in platelet-derived growth factor receptor-α...
Abstract Molecular glue degraders have emerged as a powerful class of small-molecule therapeutics, demonstrated by the clinical successes thalidomide analogs in treatment hematological malignancies. These small molecules act recruiting ubiquitin ligases to disease-relevant proteins, resulting neosubstrate ubiquitination and degradation. To date, only number ligase - interactions been exploited molecular degraders, limiting targeting scope this therapeutic modality. Covalent chemistry, which...
Abstract Recognition of aberrant gene isoforms indicative underlying DNA events can impact molecular classification and risk stratification B lymphoblastic leukemia (B-ALL). Aberrant ERG have been proposed as markers the favorable-risk DUX4 -rearranged ( r) subtype while deletion-mediated IKZF1 are associated with adverse prognosis in non- r B-ALL. The high-risk plus signature depends on deletions including PAX5 intragenic amplifications (PAX5amp) recurrent provisional B-ALL -alteration...
<div>AbstractPurpose:<p>Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) lymphoma (T-LBL) have limited therapeutic options. Clinical use of genomic profiling provides an opportunity to identify targetable alterations inform therapy.</p>Experimental Design:<p>We describe a cohort 14 pediatric patients T-ALL enrolled on the Leukemia Precision-based Therapy (LEAP) Consortium trial (NCT02670525) and patient T-LBL, discovering in...