A5074563113- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- Chronic Lymphocytic Leukemia Research
- Spectroscopy and Laser Applications
- Lymphoma Diagnosis and Treatment
- Histone Deacetylase Inhibitors Research
- Peptidase Inhibition and Analysis
- Acute Myeloid Leukemia Research
- Click Chemistry and Applications
- Chronic Myeloid Leukemia Treatments
- Cancer-related Molecular Pathways
- Multiple Myeloma Research and Treatments
- SAS software applications and methods
- Melanoma and MAPK Pathways
- Mass Spectrometry Techniques and Applications
- Chemical Synthesis and Analysis
- Immune Cell Function and Interaction
- PI3K/AKT/mTOR signaling in cancer
- Autophagy in Disease and Therapy
- Antifungal resistance and susceptibility
- CAR-T cell therapy research
- Viral-associated cancers and disorders
- Synthesis and properties of polymers
- 14-3-3 protein interactions
- PARP inhibition in cancer therapy
Harvard University
2016-2025
Dana-Farber Cancer Institute
2016-2025
Target (United States)
2023
Boston VA Research Institute
2022
Linde (United States)
2021
Longwood University
2020
Dana-Farber/Harvard Cancer Center
2016
Berry (United States)
2015
Ludwig-Maximilians-Universität München
2013
First Pavlov State Medical University of St. Petersburg
2013
Deubiquitylases (DUBs) are key regulators of the ubiquitin system which cleave moieties from proteins and polyubiquitin chains. Several DUBs have been implicated in various diseases attractive drug targets. We developed a sensitive fast assay to quantify vitro DUB enzyme activity using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Unlike other current assays, this method uses unmodified substrates, such as diubiquitin topoisomers. By analysing 42...
Abstract Multiple studies have established associations between human gut bacteria and host physiology, but determining the molecular mechanisms underlying these has been challenging 1–3 . Akkermansia muciniphila robustly associated with positive systemic effects on metabolism, favourable outcomes to checkpoint blockade in cancer immunotherapy homeostatic immunity 4–7 Here we report identification of a lipid from A. ’s cell membrane that recapitulates immunomodulatory activity cell-based...
Inhibitor of DNA binding 1 (ID1) transcription factor is essential for the proliferation and progression many cancer types, including leukemia. However, ID1 protein has not yet been therapeutically targeted in normally polyubiquitinated degraded by proteasome. Recently, it shown that USP1, a ubiquitin-specific protease, deubiquitinates rescues from proteasome degradation. Inhibition USP1 therefore offers new avenue to target cancer. Here, using ubiquitin-rhodamine-based high-throughput...
Activating mutations or structural rearrangements in BRAF are identified roughly 75% of all pediatric low-grade astrocytomas (PLGAs). However, first-generation RAF inhibitors approved for adult melanoma have poor blood-brain penetrance and only effective on tumors that express the canonical BRAFV600E oncoprotein, which functions as a monomer. These drugs (type I antagonists target "DFG-in" conformation kinase) fail to block signaling via KIAA1549:BRAF, truncation/fusion oncoprotein dimer is...
Ubiquitin specific peptidase 7 (USP7) is a deubiquitinating enzyme (DUB) that removes ubiquitin tags from protein substrates in order to alter their degradation rate and sub-cellular localization. USP7 has been proposed as therapeutic target several cancers because it many reported with role cancer progression, including FOXO4, MDM2, N-Myc, PTEN. The multi-substrate nature of USP7, combined the modest potency selectivity early generation inhibitors, presented challenge defining predictors...
Deubiquitinating enzymes (DUBs) are an emerging drug target class of ~100 proteases that cleave ubiquitin from protein substrates to regulate many cellular processes. A lack selective chemical probes impedes pharmacologic interrogation this important gene family. DUBs engage their cognate ligands through a myriad interactions. We embrace structural complexity tailor diversification strategy for DUB-focused covalent library. Pairing our library with activity-based profiling as high-density...
The related NUAK1 and NUAK2 are members of the AMPK (AMP-activated protein kinase) family kinases that activated by LKB1 (liver kinase B1) tumour suppressor kinase. Recent work suggests they play important roles in regulating key biological processes including Myc-driven tumorigenesis, senescence, cell adhesion neuronal polarity. In present paper we describe first highly specific inhibitors NUAK namely WZ4003 HTH-01-015. inhibits both isoforms (IC50 for is 20 nM 100 nM), whereas HTH-01-015...
Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number alterations. We used genome-scale shRNA viability screen cancer cell lines to systematically identify genes that are essential the context particular copy-number alterations (copy-number associated gene dependencies). The most enriched class dependencies was CYCLOPS (Copy-number Yielding Cancer Liabilities Owing Partial losS) genes, spliceosome components were prevalent. One these, pre-mRNA...
Significance Innate immune signaling has an essential role in inflammation, and dysfunction of components these pathways contributes to autoimmunity cancer. Interleukin-1 receptor-associated kinase (IRAK) family members are key mediators signal transduction by Toll-like receptors innate immunity therefore serve as potential therapeutic targets for diseases. The crystal structure the IRAK1 domain complex with a small molecule inhibitor reveals important structural details that provide...
We developed a pharmacophore model for type II inhibitors that was used to guide the construction of library kinase inhibitors. Kinome-wide selectivity profiling resulted in identification series 4-substituted 1H-pyrrolo[2,3-b]pyridines exhibited potent inhibitory activity against two mitogen-activated protein kinases (MAPKs), TAK1 (MAP3K7) and MAP4K2, as well pharmacologically interrogated such p38α (MAPK14) ABL. Further investigation structure-activity relationship (SAR) dual MAP4K2 1...
Ewing sarcoma is a pediatric cancer driven by EWS-ETS transcription factor fusion oncoproteins in an otherwise stable genomic background. The majority of tumors express wild-type TP53, and thus, therapies targeting the p53 pathway would benefit most patients. To discover targets specific for TP53 sarcoma, we used genome-scale CRISPR-Cas9 screening approach identified validated MDM2, MDM4, USP7, PPM1D as druggable dependencies. stapled peptide inhibitor MDM2 ATSP-7041, showed anti-tumor...
Deubiquitinating enzymes (DUBs), ~100 of which are found in human cells, proteases that remove ubiquitin conjugates from proteins, thereby regulating protein turnover. They involved a wide range cellular activities and emerging therapeutic targets for cancer other diseases. Drugs targeting USP1 USP30 clinical development kidney disease respectively. However, the majority substrates pathways regulated by DUBs remain unknown, impeding efforts to prioritize specific research drug development....