A5083765269- Seismic Waves and Analysis
- Earthquake Detection and Analysis
- Geophysics and Gravity Measurements
- Ionosphere and magnetosphere dynamics
- Astrophysics and Cosmic Phenomena
- HER2/EGFR in Cancer Research
- Melanoma and MAPK Pathways
- Gut microbiota and health
- Computational Drug Discovery Methods
- Synthesis and biological activity
- Methane Hydrates and Related Phenomena
- Cancer-related Molecular Pathways
- Drug Transport and Resistance Mechanisms
- Protein Kinase Regulation and GTPase Signaling
- Click Chemistry and Applications
- Pharmacological Effects and Toxicity Studies
- Cancer Mechanisms and Therapy
- Probiotics and Fermented Foods
- Advanced Proteomics Techniques and Applications
- Quinazolinone synthesis and applications
- Pediatric Hepatobiliary Diseases and Treatments
- Diet, Metabolism, and Disease
- Chronic Myeloid Leukemia Treatments
- Cell death mechanisms and regulation
- Advanced Fluorescence Microscopy Techniques
University of Michigan
2012-2024
Janssen (United States)
2024
Pacific Northwest National Laboratory
2018-2023
Washington State University Spokane
2020-2023
Battelle
2023
Georgia Highlands College
2020-2022
Northwestern University
2015
Generating highly selective probes to interrogate protein kinase function in biological studies remains a challenge, and new strategies are required. Herein, we describe the development of first cell-permeable inhibitor c-Src, key signaling cancer. Our strategy involves extension traditional design by appending functionality proposed interact with phosphate-binding loop c-Src. Using our inhibitor, demonstrate that inhibition is significantly more efficacious than pan-kinase slowing growth...
In the kinase field, there are many widely held tenets about conformation-selective inhibitors that have yet to be validated using controlled experiments. We designed, synthesized, and characterized a series of inhibitor analogues dasatinib, an FDA-approved binds active conformation. This includes two Type II bind DFG-out inactive conformation αC-helix-out Using this compounds, we analyze impact on target binding kinome-wide selectivity.
Direct-acting antivirals for the treatment of COVID-19 pandemic caused by SARS-CoV-2 virus are needed to complement vaccination efforts. Given ongoing emergence new variants, automated experimentation, and active learning based fast workflows antiviral lead discovery remain critical our ability address pandemic's evolution in a timely manner. While several such pipelines have been introduced discover candidates with noncovalent interactions main protease (Mpro), here we developed closed-loop...
On the basis of synergism observed between a selective c-Src kinase inhibitor with an HDAC inhibitor, development first chimeric and is described. The optimized shown to be potent inhibitor. Chimeric 4 further highly efficacious in cancer cell lines significantly more than dual-targeting strategy using discrete inhibitors.
Abstract Purpose: c-Src has been shown to play a pivotal role in breast cancer progression, metastasis, and angiogenesis. In the clinic, however, limited efficacy high toxicity of existing inhibitors have tempered enthusiasm for targeting c-Src. We developed novel inhibitor (UM-164) that specifically binds DFG-out inactive conformation its target kinases. hypothesized binding kinase would lead improved pharmacologic outcomes by altering noncatalytic functions targeted Experimental Design:...
The microbiota of the mammalian gut plays a dynamic role in controlling host physiology. effect activity on health is particularly evident case bile homeostasis. Bile produced by and modified microbiota, which impacts net hydrophobicity total acid pool, also modulates signaling pathways. A key mechanism modify through deconjugation salts salt hydrolase (BSH) enzymatic activity, postulated to be prerequisite for all further microbial metabolism. BSH largely considered beneficial host, genes...
The gut microbiome is a key contributor to xenobiotic metabolism. Polycyclic aromatic hydrocarbons (PAHs) are an abundant class of environmental contaminants that have varying levels carcinogenicity depending on their individual structures. Little known about how the affects rates PAH This study sought determine role has in determining various aspects metabolism liver, before and after exposure two structurally different PAHs, benzo[a]pyrene 1-nitropyrene. Following exposures, metabolic were...
We have developed a modular approach to bisubstrate inhibition of protein kinases. apply our methodology c-Src and identify highly selective inhibitor for this target. Our has yielded the most date, render cell-permeable provides valuable tool study signaling. In addition, we applied develop novel screening non-ATP-competitive inhibitors c-Src. Using methodology, discovered potent reported date. is designed be general could applicable additional kinases inhibited by promiscuous...
Diurnal rhythmicity of cellular function is key to survival for most organisms on Earth. Many circadian functions are driven by the brain, but regulation a separate set peripheral rhythms remains poorly understood. The gut microbiome potential candidate host rhythms, and this study sought specifically examine process microbial bile salt biotransformation. To enable work, an assay hydrolase (BSH) that could work with small quantities stool samples was necessary. Using turn-on fluorescence...
Abstract Microbial bile salt hydrolases (BSHs) found in the intestine catalyze deconjugation of taurine‐ and glycine‐linked salts produced liver. The resulting are biological detergents critical aiding lipophilic nutrient digestion. Therefore, activity BSHs gut microbiome is directly linked to human metabolism overall health. Bile has also been associated with disease phenotypes such as liver colorectal cancer. In order reshape optimize metabolism, tools characterize quantify these processes...
Subcellular localization is important in regulating kinase activation and function. Small molecule flu-orescent probes for kinases can provide compli-mentary advantages to immunofluorescence genetically encoded tags. Here, we developed a highly selective fluorescent probe c-Src, non-receptor tyrosine kinase. Our combines py-razolopyrimidine (PP) binding group coumarin fluorophore, covalently binds c-Src through non-conserved cysteine (Cys-280). PP-coumarin (PP-C) turn-on fluo-rescent of that...
Abstract Animals produce bile to act as an antibacterial agent and maximize the absorption of lipophilic nutrients in gut. The physical properties are largely dictated by amphipathic salt molecules, which also participate signaling pathways modulating physiological processes upon binding host receptors. Upon excretion salts from gall bladder into intestine, gut microbiota can create metabolites with modified capabilities. category magnitude metabolism have positive or negative effects on...
Even as the field of microbiome research has made huge strides in mapping microbial community composition a variety environments and organisms, explaining phenotypic influences on host by taxa – both known unknown their specific functions still remain major challenges. A pressing need is ability to assign terms enzymes small molecules or groups community. This knowledge will be crucial for advancing personalized therapies based targeted modulation microbes metabolites that have predictable...
Photoaffinity labeling (PAL) methodologies have proven to be instrumental for the unbiased deconvolution of protein-ligand binding events in physiologically relevant systems. However, like other chemical proteomic workflows, they are limited many ways by time-intensive sample manipulations and data acquisition techniques. Here, we describe an approach address this challenge through innovation a carboxylate bead-based protein cleanup procedure remove excess small-molecule contaminants couple...
Abstract Src is a non-receptor tyrosine kinase, which acts as an integrator of diverse signaling pathways used by cancer cells for cell proliferation, migration and metastasis. Recent interest in developing target specific therapy improved benefits with manageable toxic effects has sharply increased the testing new family kinase inhibitors their potential anticancer therapeutic properties. In this study, we sought to investigate chemical characteristics biological novel inhibitor KB-164,...
<p>Supplementary Figure S1. Biochemical data for UM-164 and dasatinib. Supplementary S2. Western blots showing the expression of P-Src, P-EGFR P-p38MAPK in selected TNBC cell lines. S3. is a dual c-Src/p38 kinase inhibitor lysate. S4. Signaling pathway analysis SUM 149 cells when treated with dasatinib or at their IC50 values (630 nM 230 nM, respectively). S5. Effect on invasion alone plus p38MAPK inhibitor, BIRB-796. S6. combination inhibitors level P-EGFR/Tyr1068 P-p38MAPK. S7....
<p>Detailed experimental information for: Cell cycle analysis; Dose response studies; Western blot analyses; 3D cell culture; Bead motility assay; invasion assays; General synthetic methods; Synthesis of UM-164.</p>
<p>Legends associated with Supplementary Figures S1-S12.</p>