A5003360439- Immune cells in cancer
- Cancer Cells and Metastasis
- Monoclonal and Polyclonal Antibodies Research
- RNA modifications and cancer
- Immunotherapy and Immune Responses
- Cancer Research and Treatments
- Immune Cell Function and Interaction
- Cancer Immunotherapy and Biomarkers
- MicroRNA in disease regulation
- Glycosylation and Glycoproteins Research
- Nitric Oxide and Endothelin Effects
- Nanoplatforms for cancer theranostics
- CAR-T cell therapy research
- Chronic Lymphocytic Leukemia Research
- Hemoglobin structure and function
- Cancer Mechanisms and Therapy
- Ferroptosis and cancer prognosis
- Immunodeficiency and Autoimmune Disorders
- Chemical Synthesis and Analysis
- Extracellular vesicles in disease
- Macrophage Migration Inhibitory Factor
- Neuroscience and Neuropharmacology Research
- Cell Adhesion Molecules Research
- Click Chemistry and Applications
- RNA and protein synthesis mechanisms
Bicycle Therapeutics (United Kingdom)
2022-2024
Merck & Co., Inc., Rahway, NJ, USA (United States)
2004-2024
United States Military Academy
2003-2011
University of Southampton
1994-2004
University of Michigan
1998-2002
University of California, Berkeley
2002
Howard Hughes Medical Institute
1998-2000
Michigan State University
2000
Cancer-associated fibroblasts (CAF) represent a functionally heterogeneous population of activated that constitutes major component tumor stroma. Although CAFs have been shown to promote growth and mediate resistance chemotherapy, the mechanisms by which they may contribute immune suppression within microenvironment (TME) in lung squamous cell carcinoma (LSCC) remain largely unexplored. Here, we identified positive correlation between CAF monocytic myeloid abundances 501 primary LSCCs mining...
Abstract Cancer immunotherapy has revolutionized the treatment of lung adenocarcinoma (LUAD); however, a significant proportion patients do not respond. Recent transcriptomic studies to understand determinants response have pinpointed stromal-mediated resistance mechanisms. To gain better understanding stromal biology at cellular and molecular level in LUAD, we performed single-cell RNA sequencing 256,379 cells, including 13,857 mesenchymal from 9 treatment-naïve patients. Among cell...
Nitric oxide (NO) functions as a signaling agent by activation of the soluble isoform guanylate cyclase (sGC), heterodimeric hemoprotein. NO binds to heme sGC and triggers formation cGMP from GTP. Here we report direct kinetic measurements multistep binding correlate these presteady state events with enzyme catalysis. form six-coordinate, nonactivated, intermediate ( k on > 1.4 × 10 8 M −1 ⋅s at 4°C). Subsequent release axial histidine ligand is shown be molecular step responsible for...
The molecular and neuronal substrates conferring on clozapine its unique superior efficacy in the treatment of schizophrenia remain elusive. interaction with many G protein-coupled receptors is well documented but less known about biologically active metabolite, N -desmethylclozapine. Recent clinical preclinical evidences antipsychotic activity muscarinic agonist xanomeline prompted us to investigate effects -desmethylclozapine cloned human M1-M5 receptors. preferentially bound M1 an IC 50...
The heme in soluble guanylate cyclases (sGC) as isolated is ferrous, high-spin, and 5-coordinate. [1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one] (ODQ) has been used extensively a specific inhibitor for sGC diagnostic tool identifying role signal transduction events. Addition of ODQ to ferrous leads Soret shift from 431 392 nm decrease nitric oxide (NO)-stimulated activity. This consistent with oxidation the ferric heme. results reported here further define molecular mechanism inhibition by...
Using a continuous fluorescence-based enzyme assay, we have characterized the antibacterial agents tumicamycin and liposidomycin B as inhibitors of solubilized Escherichia coli phospho-N-acetylmuramyl-pentapeptide translocase. Tunicamycin exhibited reversible inhibition (Ki = 0.55 +/- 0.1 microM) which was noncompetitive with respect to lipid acceptor substrate competitive fluorescent analog, dansyl-UDPMurNAc-pentapeptide. Liposidomycin slow-binding 80 15 nM) These results provide insight...
As part of an effort to examine the utility antibody–drug conjugates (ADCs) beyond oncology indications, a novel pyrophosphate ester linker was discovered enable targeted delivery glucocorticoids. small molecules, these highly soluble phosphate drug linkers were found have ideal orthogonal properties: robust plasma stability coupled with rapid release payload in lysosomal environment. Building upon findings, site-specific ADCs made between this combination and antibody against human CD70,...
Soluble guanylate cyclase (sGC) is a ferrous iron hemoprotein receptor for nitric oxide (NO). NO binding to the heme activates enzyme 300-fold. sGC as isolated five-coordinate, with histidine axial ligand. The NO-activated five-coordinate nitrosyl complex where bond broken. Past studies using rapid-reaction kinetics demonstrated that both formation of six-coordinate intermediate and conversion activated depended on concentration NO. A model invoking second molecule catalyst sGC–NO was...
In an effort to examine the utility of antibody–drug conjugates (ADCs) beyond oncology indications, a novel phosphate bridged Cathepsin B sensitive linker was developed enable targeted delivery glucocorticoids. Phosphate bridging linkers allows for payload attachment at aliphatic alcohol. As small molecule drug-linkers, these aqueous soluble containing drug-linkers were found have robust plasma stability coupled with rapid release in lysosomal environment. Site-specific ADCs successfully...
Myeloid-derived suppressor cells (MDSC) are immature myeloid that accumulate in the tumor microenvironment (TME). MDSCs have been shown to dampen antitumor immune responses and promote growth; however, mechanisms of MDSC induction their role promoting suppression cancer remain poorly understood. Here, we characterized phenotype function monocytic (M-MDSC) generated by coculture human peripheral blood mononuclear with SK-MEL-5 vitro. We selected melanoma cell line generate M-MDSCs because...
Glucocorticoids (GCs) are excellent anti-inflammatory drugs but dose-limited by on-target toxicity. We sought to solve this problem delivering GCs immune cells with antibody–drug conjugates (ADCs) using antibodies containing site-specific incorporation of a non-natural amino acid, novel linker chemistry for in vitro and vivo stability, existing glucocorticoid receptor (GR) agonists as payloads. directed fluticasone propionate human antigen-presenting afford GR activation that was dependent...
Soluble guanylate cyclase (sGC) catalyzes the conversion of GTP to cGMP and is activated several hundred-fold by binding nitric oxide (*NO) heme prosthetic group. We have examined stability nitrosyl-heme complex sGC (*NO-sGC) at 37 degreesC in order determine whether simple dissociation *NO from could account for observed vivo deactivation time. Recombinant was purified Sf9 cells coinfected with baculoviruses containing cDNAs alpha1 beta1 subunits rat lung sGC. The protein contained a...
The enzyme-soluble guanylate cyclase (sGC), which converts GTP to cGMP, is a receptor for the signaling agent nitric oxide (NO). YC-1, synthetic benzylindazole derivative, has been shown activate sGC in an NO-independent fashion. In presence of carbon monoxide (CO), by itself activates approximately 5-fold, YC-1 level comparable stimulation NO alone. We have used kinetic analyses and resonance Raman spectroscopy (RR) investigate interaction CO with cyclase. 200 μM Vmax/Km increases 226-fold....
Phospho-N-acetyl-muramyl-pentapeptide translocase (translocase 1) catalyzes the first of a sequence lipid-linked steps that ultimately assemble peptidoglycan layer bacterial cell wall. This essential enzyme is target several natural product antibiotics and has recently been focus antimicrobial drug discovery programs. The catalytic mechanism 1 believed to proceed via covalent intermediate formed between phospho-N-acetyl-muramyl-pentapeptide nucleophilic amino acid residue. Amino alignments...
Background In contrast to immune checkpoint inhibitors, the use of antibodies as agonists costimulatory receptors cancer therapeutics has largely failed. We sought address this problem using a new class modular synthetic drugs, termed tumor-targeted cell (TICAs), based on constrained bicyclic peptides ( Bicycles ). Methods Phage libraries displaying were panned for binders against tumor necrosis factor (TNF) superfamily CD137 and OX40, antigens EphA2, Nectin-4 programmed death ligand 1. The...
Enzymes are often considered less "druggable" targets than ligand-regulated proteins such as G-protein-coupled receptors, ion channels, or other hormone receptors. Reasons for this include cellular location (intracellular vs. cell surface), typically lower affinities the binding of small molecules compared to ligand-specific and (catalytic) sites that charged highly polar. A practical drawback discovery compounds targeting enzymes is screening compound libraries carried out in cell-free...
Bruton's tyrosine kinase (BTK) is a Tec family with well-defined role in the B cell receptor (BCR) pathway. It has become an attractive target for selective inhibition and treatment of related diseases. We report series compounds based on 8-amino-imidazo[1,5-a]pyrazine that are potent reversible BTK inhibitors excellent selectivity. Selectivity achieved through specific interactions ligand hinge driven by aminopyridine hydrogen bondings Ser538 Asp539, hydrophobic interaction...
Background CD137 (4-1BB) is an immune costimulatory receptor with high therapeutic potential in cancer. We are creating tumor target-dependent agonists using a novel chemical approach based on fully synthetic constrained bicyclic peptide ( Bicycle® ) technology. Nectin-4 overexpressed multiple human cancers that may benefit from agonism. To this end, we have developed BT7480, novel, first-in-class, Nectin-4/CD137 Bicycle tumor-targeted cell agonist™ TICA™). Methods and co-expression analyses...