A5039471153- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- Peptidase Inhibition and Analysis
- Carbohydrate Chemistry and Synthesis
- Protein Kinase Regulation and GTPase Signaling
- Bioactive Compounds and Antitumor Agents
- X-ray Diffraction in Crystallography
- Glycosylation and Glycoproteins Research
- Melanoma and MAPK Pathways
- Genetics and Neurodevelopmental Disorders
- Histone Deacetylase Inhibitors Research
- Crystallization and Solubility Studies
- Cancer Mechanisms and Therapy
- Enzyme Catalysis and Immobilization
- Synthesis and biological activity
- Radiomics and Machine Learning in Medical Imaging
- Chemical Synthesis and Analysis
- Microbial Natural Products and Biosynthesis
- Machine Learning in Materials Science
- PI3K/AKT/mTOR signaling in cancer
- Endoplasmic Reticulum Stress and Disease
- Marine Sponges and Natural Products
- Multiple Myeloma Research and Treatments
- Surfactants and Colloidal Systems
- Protein Tyrosine Phosphatases
Purdue University West Lafayette
2018-2025
National Institutes of Health
2024-2025
National Cancer Institute
2024-2025
Center for Cancer Research
2024-2025
California Polytechnic State University
2014
Dysregulation of the ubiquitin-proteasome systems is a hallmark various disease states including neurodegenerative diseases and cancer. Ubiquitin C-terminal hydrolase L1 (UCHL1), deubiquitinating enzyme, expressed primarily in central nervous system under normal physiological conditions, however, considered an oncogene cancers, melanoma, lung, breast, lymphoma. Thus, UCHL1 inhibitors could serve as viable treatment strategy against these aggressive cancers. Herein, we describe covalent...
Immunoproteasome (iCP) is a proteasome isoform that expressed under inflammatory conditions such as cytokine interferon-γ exposure. The iCP has different catalytic subunits other than the standard CP (standard core particle), allowing production of major histocompatibility complex class I (MHC-I) compatible peptides for eventual T-cell activation. We have previously reported design fluorescent probe monitors activity in cells called TBZ-1, and we applied TBZ-1's recognition sequence prodrug...
Optimization of a series aryl urea RAF inhibitors led to the identification type II pan-RAF inhibitor GNE-0749 (7), which features fluoroquinazolinone hinge-binding motif. By minimizing reliance on common polar hinge contacts, this binder allows for greater contribution RAF-specific residue interactions, resulting in exquisite kinase selectivity. Strategic substitution fluorine at C5 position efficiently masked adjacent NH functionality and increased solubility by impeding solid-state...
The proteasome degrades proteins, which is essential for cellular homeostasis. Ubiquitin independent proteolysis highly disordered and misfolded proteins. A decline of proteasomal activity has been associated with multiple neurodegenerative diseases due to the accumulation In this work, cyclic peptide stimulators (CyPPSs) that enhance clearance proteins were discovered. initial screen predicted natural products (pNPs), several peptides found stimulate 20S core particle (20S CP). Development...
Conformational switching is pervasively driven by protein interactions, particularly for intrinsically disordered binding partners. We developed a dually orthogonal fluorescence-based assay to monitor such events, exploiting environmentally sensitive fluorophores. This applied E3 ligase E6AP, as its AZUL domain induces disorder-to-order switch in an region of the proteasome, so-named Rpn10 AZUL-binding (RAZUL). By testing various fluorophores, we appropriate high-throughput screening...
The deubiquitinating enzyme (DUB) UCHL1 is implicated in various disease states including neurodegenerative and cancer. However, there a lack of quality probe molecules to gain better understanding on biology. To this end study was carried out fully characterize optimize the irreversible covalent inhibitor VAEFMK. Structure-activity relationship studies identified modifications improve activity versus target full cellular characterization for first time with scaffold. produced new inhibitor,...
Regulator of G protein signaling (RGS) proteins are negative modulators that have emerged as promising drug targets to improve specificity and reduce side effects protein–coupled receptor–related therapies. Several small molecule RGS inhibitors been identified; however, enhancing function is often more clinically desirable but presents a challenge. Low levels RGS2 associated with various pathologies, including hypertension heart failure. For this reason, prominent example wherein its would...
Abstract Cancer immunotherapy refers to the approach leveraging patients’ immune system against tumor, which has gained tremendous progress hallmarked by checkpoint blockade and adoptive cell therapies. However, contemporary strategies suffer from limited responses, adverse side effects, low tissue penetration due utilization of macromolecules, calling for more efficacious safer alternative strategies. SHP1 is a protein tyrosine phosphatase (PTP) primarily expressed in hematopoietic cells...
Structure-based optimization of a set aryl urea RAF inhibitors has led to the identification Type II pan-RAF inhibitor GNE-9815 (7), which features unique pyrido[2,3-d]pyridazin-8(7H)-one hinge-binding motif. With minimal polar hinge contacts, pyridopyridazinone binder moiety affords exquisite kinase selectivity in lipophilic efficient manner. The improved physicochemical properties provided path for oral dosing without enabling formulations. In vivo evaluation combination with MEK...
Abstract Sugar oxime ether surfactants are a new class of produced by the reaction sugar with hydrophobic alkoxyamine, producing an linkage. We examined nine examples this surfactants. The sugars used were maltose, sucrose, and glyceraldehyde; alkoxyamines decyloxyamine, dodecyloxya mine, adamantyloxyamine. For resulting we determined their thermal stability, melting point, water solubility, effect on surface tension, critical micelle concentration. found that all compounds tested thermally...