A5000957789- PI3K/AKT/mTOR signaling in cancer
- Chemical Synthesis and Analysis
- RNA and protein synthesis mechanisms
- Ubiquitin and proteasome pathways
- Click Chemistry and Applications
- Protein Degradation and Inhibitors
- RNA Interference and Gene Delivery
- Cancer-related Molecular Pathways
- Monoclonal and Polyclonal Antibodies Research
- MicroRNA in disease regulation
- CRISPR and Genetic Engineering
- Microtubule and mitosis dynamics
- RNA Research and Splicing
- Carbohydrate Chemistry and Synthesis
- Microbial Natural Products and Biosynthesis
- 14-3-3 protein interactions
- Cancer-related gene regulation
- Multiple Myeloma Research and Treatments
- Advanced biosensing and bioanalysis techniques
- RNA modifications and cancer
- Cancer-related molecular mechanisms research
University of Michigan
2017-2024
Ann Arbor Center for Independent Living
2019
Discovery and structure elucidation of natural products available in infinitesimally small quantities are recognized challenge. This challenge is epitomized by the diphenazine class molecules that contain three bridged stereocenters, several conformations, ring fusions, multiple spatially isolated phenols. Because empirical NMR spatial analyses using ROESY/NOESY were unsuccessful tackling these challenges, we developed a computational pipeline to determine relative absolute configurations...
Eukaryotic translation initiation factor 4E (eIF4E) is an RNA-binding protein that binds to the m7GpppX-cap at 5′ terminus of coding mRNAs initiate cap-dependent translation. While all cells require translation, cancer become addicted enhanced translational capacity, driving production oncogenic proteins involved in proliferation, evasion apoptosis, metastasis, and angiogenesis, among other cancerous phenotypes. eIF4E rate-limiting factor, its activation has been shown drive initiation,...
In a high-throughput screening campaign, we recently discovered the rRNA-binding tetracyclines, methacycline and meclocycline, as inhibitors of Dicer-mediated processing microRNAs. Herein, describe our biophysical biochemical characterization these compounds. Interestingly, although direct, albeit weak, binding to pre-microRNA hairpins was observed, inhibitory activity compounds not due RNA binding. Through additional chemical studies, revealed that metal chelation likely plays principle...
Protein disorder plays a crucial role in signal transduction and is key for many cellular processes including transcription, translation, cell cycle. Within the intrinsically disordered protein interactome, α-helix commonly used binding, which induced via disorder-to-order transition. Because targeting of protein-protein interactions (PPIs) remains an important challenge medicinal chemistry, efforts have been made to mimic this secondary structure rational inhibitor design through use...
Human biology is regulated by a complex network of protein–protein interactions (PPIs), and disruption this has been implicated in many diseases. However, the targeting PPIs remains challenging area for chemical probe drug discovery. Although methodologies have put forth to facilitate these efforts, new technologies are still needed. Current biochemical assays typically limited motif–domain domain–domain interactions, that will enable screening full-length protein systems, which more...
Hydrocarbon stapled (HCS) peptides are a class of cross-linked α-helix mimetics. The technology relies on the use α,α'-disubstituted alkenyl amino acids, which fully contrain helical region to typically yield with enhanced structural ordering and biological activity. Recently, monosubstituted acids were disclosed for peptide stapling; however, impact that this tether has HCS structure activity not yet been explored. By applying disordered eIF4E-binding protein 1 (4E-BP1), we discovered type...
MicroRNAs (miRNAs) are a family of small noncoding RNAs that regulate gene expression. Due to their important activity in the fine-tuning protein translation, abnormal expression miRNAs has been linked many human diseases, making targeting attractive as novel therapeutic strategy. Accordingly, researchers have heavily engaged discovery molecule modulators miRNAs. With an interest identification new chemical space for miRNAs, we developed high-throughput screening (HTS) technology, catalytic...
Dysregulation of translation is a hallmark cancer that enables rapid changes in cellular protein production to shape oncogenic phenotypes. Translation initiation governed by the m7GpppX cap-binding eukaryotic factor 4E (eIF4E), rate-limiting cap-dependent initiation. eIF4E overexpressed many cancers and drives oncoproteins promote tumor growth survival. Accordingly, has been established as an attractive albeit challenging therapeutic target. Building upon our previous work developing...
Eukaryotic translation initiation factor 4E (eIF4E) is an RNA-binding protein that binds to the m
Dicer is an RNase III enzyme that responsible for the maturation of small RNAs such as microRNAs. As Dicer's cleavage products play key roles in promoting cellular homeostasis through fine-tuning gene expression, dysregulation activity can lead to several human diseases, including cancers. Mutations have been found induce tumorigenesis and development a rare pleiotropic tumor predisposition syndrome children young adults called DICER1 syndrome. These patients harbor germline somatic...
Melanoma is the deadliest form of skin cancer with a 5-year survival rate less than 20%. While significant strides have been made in field kinase-targeted and immune-based therapies for melanoma, development resistance to these therapeutic agents has hindered success treatment. Drug-resistant melanoma particularly reliant on enhanced cap-dependent translation drive production oncoproteins that promote growth survival. The m
Phosphorylation of translational repressor eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) controls the cap-dependent translation, a type synthesis that is frequently upregulated in human diseases such as cancer. Because its critical cellular function, it not surprising multiple kinases can post-translationally modify 4E-BP1 to drive aberrant translation. We recently reported site-selective chemoproteomic method for uncovering kinase-substrate interactions, and...
Recent estimates of the human proteome suggest that there are ~20,000 protein-coding genes, protein products which contain >145,000 phosphorylation sites. Unfortunately, in-depth examination phosphoproteome has far outpaced ability to annotate kinases mediate these post-translational modifications. To obtain actionable information about phosphorylation-driven signaling cascades, it is essential identify responsible for phosphorylating sites differ across disease states. fill in knowledge...