A5014471208- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Advanced Proteomics Techniques and Applications
- Biochemical and Molecular Research
- Peptidase Inhibition and Analysis
- Click Chemistry and Applications
- Mass Spectrometry Techniques and Applications
- RNA Research and Splicing
- Multiple Myeloma Research and Treatments
- Bacterial biofilms and quorum sensing
- Cancer-related gene regulation
- Glycosylation and Glycoproteins Research
- Radiopharmaceutical Chemistry and Applications
- Histone Deacetylase Inhibitors Research
- Microfluidic and Capillary Electrophoresis Applications
- Antimicrobial Peptides and Activities
- Hippo pathway signaling and YAP/TAZ
- RNA and protein synthesis mechanisms
- Antibiotic Resistance in Bacteria
- Molecular Biology Techniques and Applications
Dana-Farber Cancer Institute
2022-2025
Target (United States)
2023
Boston University
2023
Dana-Farber Brigham Cancer Center
2022
Brigham and Women's Hospital
2022
Harvard University
2022
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...
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...
Transcriptional enhanced associate domain (TEAD) proteins together with their transcriptional coactivator yes-associated protein (YAP) and the PDZ-binding motif (TAZ) are important transcription factors cofactors that regulate gene expression in Hippo pathway. In mammals, TEAD families have four homologues: TEAD1 (TEF-1), TEAD2 (TEF-4), TEAD3 (TEF-5), TEAD4 (TEF-3). Aberrant hyperactivation of TEAD/YAP signaling been implicated a variety malignancies. Recently, TEADs were recognized as being...
A systematic strategy to develop dual-warhead inhibitors is introduced circumvent the limitations of conventional covalent such as vulnerability mutations corresponding nucleophilic residue. Currently, all FDA-approved small molecules feature one electrophile, leaving open a facile route acquired resistance. We conducted analysis human proteins in protein data bank reveal ∼400 unique targets amendable dual inhibitors, which we term "molecular bidents". demonstrated this by targeting two...
We describe a complete open-source hardware/software solution for high performance thermostatted peptide fraction collection to support mass spectrometry experiments with complex proteomes. The instrument is easy assemble using parts readily available through retail channels at of the cost compared typical commercial systems. Control software written in Python allowing rapid customization. demonstrate several useful applications, including automated deposition LC separated peptides...
ABSTRACT The eukaryotic RNA polymerase II (Pol II) multi-protein complex transcribes mRNA and coordinates several steps of co-transcriptional processing chromatin modification. largest Pol subunit, Rpb1, has a C-terminal domain (CTD) comprising dozens repeated heptad sequences (Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7), each containing five phospho-accepting amino acids. CTD heptads are dynamically phosphorylated, creating specific patterns correlated with transcription initiation, elongation,...
The family of deubiquitinases (DUBs) comprises ∼100 enzymes that cleave ubiquitin from substrate proteins and thereby regulate key aspects human physiology. DUBs have recently emerged as disease-relevant chemically tractable, although currently there are no approved DUB-targeting drugs most preclinical small molecules low-potency and/or multitargeted. We paired a novel capillary electrophoresis microchip containing an integrated, "on-chip" C18 bed (SPE-ZipChip) with TMT version our described...
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...
Target-based screening of covalent fragment libraries with mass spectrometry has emerged as a powerful strategy to identify chemical starting points for small molecule inhibitors or find new binding pockets on proteins interest. These span diverse space modest number compounds. Screening fragments against purified protein targets reduces the demands spectrometer respect absolute throughput, detection limit, and dynamic range. Given these relaxed analytical requirements, we sought develop an...