A5041835523- Protein Degradation and Inhibitors
- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- Multiple Myeloma Research and Treatments
- RNA modifications and cancer
- Ubiquitin and proteasome pathways
- Computational Drug Discovery Methods
- Chemical Synthesis and Analysis
- Peptidase Inhibition and Analysis
- Cell Image Analysis Techniques
- Click Chemistry and Applications
- RNA Interference and Gene Delivery
- Neurogenetic and Muscular Disorders Research
- Autophagy in Disease and Therapy
- Chromatin Remodeling and Cancer
- HIV/AIDS drug development and treatment
- Microbial Natural Products and Biosynthesis
- CRISPR and Genetic Engineering
- interferon and immune responses
- Innovative Microfluidic and Catalytic Techniques Innovation
- Mosquito-borne diseases and control
- Advanced biosensing and bioanalysis techniques
- Genomics and Phylogenetic Studies
- Histone Deacetylase Inhibitors Research
- Bacterial Genetics and Biotechnology
Novartis (United States)
2014-2025
Novartis (China)
2024
The Ohio State University
2024
Novartis (Switzerland)
2014-2023
Novartis Institutes for BioMedical Research
2018-2023
University of California, Berkeley
2019
Vertex Pharmaceuticals (United States)
2018
University of Oxford
2018
Boston Biomedical Research Institute
2018
Goethe University Frankfurt
2018
Targeted protein degradation has arisen as a powerful strategy for drug discovery allowing the targeting of undruggable proteins proteasomal degradation. This approach most often employs heterobifunctional degraders consisting protein-targeting ligand linked to an E3 ligase recruiter ubiquitinate and mark interest One challenge with this approach, however, is that only few recruiters currently exist targeted applications, despite hundreds known ligases in human genome. Here, we utilized...
Targeted protein degradation (TPD) mediates level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only few have been utilized TPD. Interestingly, the workhorse ligase CRBN observed be downregulated settings resistance immunomodulatory inhibitory drugs (IMiDs). Here we show that essential receptor DCAF1 can harnessed utilizing selective,...
Abstract Cultivation of myxobacteria the Nannocystis genus led to isolation and structure elucidation a class novel cyclic lactone inhibitors elongation factor 1. Whole genome sequence analysis annotation enabled identification putative biosynthetic cluster synthesis process. In biological assays compounds displayed anti‐fungal cytotoxic activity. Combined genetic proteomic approaches identified eukaryotic translation 1α (EF‐1α) as primary target for this compound class. Nannocystin A ( 1 )...
The targeting of one mRNA in the transcriptome requires small molecules that bind with substantial affinity and specificity. As such, compounds specificity for individual RNA secondary structural motifs could be useful RNA. Described herein is synthesis a combinatorial library 105 dimers deoxystreptamine subsequent identification specific hairpin loop sizes, including tetraloops octaloops. Such will perturbation function vivo.
Targeted degradation of proteins through the ubiquitin-proteasome system (UPS) via activities E3 ubiquitin ligases regulates diverse cellular processes, and misregulation these enzymes contributes to pathogenesis human diseases. One challenges facing UPS field is delineate complete cohort substrates for a particular ligase. Advances in mass spectrometry development antibodies recognizing Lys-ϵ-Gly-Gly (diGly) remnant from ubiquitinated following trypsinolysis have provided tool address this...
Abstract Malaria continues to be one of the most devastating human diseases despite many efforts limit its spread by prevention infection or pharmaceutical treatment patients. We have conducted a screen for antiplasmodial compounds using natural product library. Here we report on cyclomarin A as potent growth inhibitor Plasmodium falciparum and identification molecular target, diadenosine triphosphate hydrolase (PfAp3Aase), chemical proteomics. Using biochemical assay, could show that is...
PHY34 is a synthetic small molecule, inspired by compound naturally occurring in tropical plants of the Phyllanthus genus. was developed to have potent vitro and vivo anticancer activity against high grade serous ovarian cancer (HGSOC) cells. Mechanistically, induced apoptosis cells late-stage autophagy inhibition. Furthermore, significantly reduced tumor burden xenograft model cancer. In order identify its molecular target/s, we undertook an unbiased approach utilizing mass...
Abstract Chemogenomic profiling is a powerful and unbiased approach to elucidate pharmacological targets the mechanism of bioactive compounds. Until recently, genome-wide, high-resolution experiments this nature have been limited fungal systems due lack mammalian genome-wide deletion collections. With example novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, we demonstrate that CRISPR/Cas9 system enables generation transient homo- heterozygous libraries allows for...
Splice modulating small molecules have been developed to promote the U1 snRNP engage with pre-mRNAs strong and altered sequence preference. Transcriptomic profiling of bulk RNA from compound treated cells enables detection RNAs impacted; however, it is difficult delineate whether transcriptional changes are a consequence direct treatment or trans-acting effects. To identify targets that bind directly splice compounds, we deployed photoaffinity labeling (PAL)-based Chem-CLIP approach. Through...
RNA is known to have multiple roles in critical cellular functions. Thus, there great potential for RNA-binding small molecules as both therapeutic agents and probes. Unfortunately, the secondary structures that can adopt caused difficulty development of a general paradigm RNA−small molecule binding. In particular, standard compounds such aminoglycosides do not generally bind hairpin loops, widespread vitally important structural motif. this manuscript we report dimers deoxystreptamine loops...
Phenotypic assays have become an established approach to drug discovery. Greater disease relevance is often achieved through cellular models with increased complexity and more detailed readouts, such as gene expression or advanced imaging. However, the intricate nature cost of these impose limitations on their screening capacity, restricting screens well-characterized small compound sets chemogenomics libraries. Here, we outline a cheminformatics identify set compounds likely novel...
A major mechanism for bacterial resistance to antibiotics is through the acquisition of a plasmid coding resistance-mediating proteins. Described herein strategy eliminate these plasmids from bacteria, thus resensitizing bacteria antibiotics. This approach involves mimicking natural elimination, known as incompatibility. The compound apramycin was identified tight binder SLI RNA (Kd = 93 nM), in vivo target incompatibility determinate I, and footprinting/mutagenesis studies indicate binds...
Elucidation of the molecular forces governing small molecule−RNA binding is paramount to progress rational design strategies. The extensive characterization aminoglycoside−16S rRNA A-site interaction has deepened our understanding how aminoglycosides bind their target and exert antimicrobial effects. However, date no other RNA compounds have undergone such rigorous evaluation, in general origins remain a mystery. We recently reported identification molecules, dimers 2-deoxystreptamine, which...
We screened a library of bioactive small molecules for activators and inhibitors innate immune signaling through IRF3 NFkB pathways with the goals advancing pathway understanding discovering probes immunology research. used high content screening to measure translocation from cytoplasm nucleus in primary human macrophages; these transcription factors play critical role activation STING other pro-inflammatory pathways. Our activator screen yielded diverse set hits that promoted nuclear and/or...