A5067237562- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- Amino Acid Enzymes and Metabolism
- Protein Degradation and Inhibitors
- Monoclonal and Polyclonal Antibodies Research
- Histone Deacetylase Inhibitors Research
- Endoplasmic Reticulum Stress and Disease
- Cancer-related Molecular Pathways
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Microbial Natural Products and Biosynthesis
- CAR-T cell therapy research
- Cancer Genomics and Diagnostics
- SARS-CoV-2 detection and testing
- Metabolism and Genetic Disorders
- Acute Myeloid Leukemia Research
- Multiple Myeloma Research and Treatments
- Nitric Oxide and Endothelin Effects
- Immunotherapy and Immune Responses
- SARS-CoV-2 and COVID-19 Research
- Cancer Immunotherapy and Biomarkers
- Biosensors and Analytical Detection
- Cell death mechanisms and regulation
- Drug Transport and Resistance Mechanisms
- Cancer Research and Treatments
- Glycosylation and Glycoproteins Research
Xilio Therapeutics (United States)
2021-2024
University of Chicago
2021-2024
Cornell University
1996-2023
Massachusetts General Hospital
2018-2022
Harvard University
2018-2022
Merck & Co., Inc., Rahway, NJ, USA (United States)
2018-2022
Center for Cancer Research
2021
Progenra (United States)
2007-2016
Old Dominion University
2015
Durham VA Medical Center
2015
Metastasis: A matter of translation? Solid tumors shed a small number cancer cells into the bloodstream, some which are believed to contribute metastasis. The molecular features that confer these circulating tumor (CTCs) with metastatic potential poorly understood. Ebright et al. studied CTCs from breast patients and found increased expression levels certain ribosomal proteins regulators translation had greater capacity in mouse model (see Perspective by Ma Jeffrey). Consistent this finding,...
The diketopiperazine NPI-2358 is a synthetic analog of NPI-2350, natural product isolated from Aspergillus sp., which depolymerizes microtubules in A549 human lung carcinoma cells. Although structurally different the colchicine-binding site agents reported to date, binds tubulin. has potent in-vitro anti-tumor activity against various tumor cell lines and maintains with multidrug-resistant (MDR) profiles. In addition, when evaluated proliferating umbilical vein endothelial cells (HUVECs),...
Salinosporamide A (1, NPI-0052) is a potent proteasome inhibitor in development for treating cancer. In this study, series of analogues was assayed cytotoxicity, inhibition, and inhibition NF-kappaB activation. Marked reductions potency cell-based assays accompanied replacement the chloroethyl group with unhalogenated substituents. Halogen exchange cyclohexene ring epoxidation were well tolerated, while some stereochemical modifications significantly attenuated activity. These findings...
The aberrant production of nitric oxide (NO) contributes to the pathogenesis diseases as diverse cancer and arthritis. Sustained NO via inducible enzyme, nitric-oxide synthase 2 (NOS2), requires extracellular arginine uptake. Three closely related cationic amino acid transporter genes (Cat1–3) encode transporters that mediate most uptake in mammalian cells. Because CAT2 is induced coordinately with NOS2 numerous cell types, we investigated a possible role for CAT2-mediated transport...
Inhibitors of the cancer-related cysteine isopeptidase human ubiquitin-specific proteases 7 (USP7) and 47 (USP47) are considered to have potential as cancer therapeutics, owing their ability stabilize tumor suppressor p53 decrease DNA polymerase β (Polβ), both which anticancer effects. A new class dual small molecule inhibitors these enzymes has been discovered. Compound 1, a selective inhibitor USP7 USP47 with moderate potency, demonstrates inhibition in cells induces elevated apoptosis...
Foxp3+ T-regulatory (Treg) cells are known to suppress protective host immune responses a wide variety of solid tumors, but their therapeutic targeting is largely restricted transient depletion or "secondary" modulation, e.g. using anti-CTLA-4 monoclonal antibody. Our ongoing studies the post-translational modifications that regulate Foxp3 demonstrated histone/protein acetyltransferase, Tip60, plays dominant role in promoting acetylation, dimerization and function Treg cells. We now show...
A strain of Streptomyces nodosus (NPS007994) isolated from a marine sediment collected in Scripps Canyon, La Jolla, California, was found to produce lajollamycin (1), nitro-tetraene spiro-beta-lactone-gamma-lactam antibiotic. The structure established by complete analysis spectroscopic data and comparison with known antibiotics oxazolomycin (2), 16-methyloxazolomycin (3), triedimycin B (4). Lajollamycin (1) showed antimicrobial activity against both drug-sensitive -resistant Gram-positive...
Conjugation or deconjugation of ubiquitin (Ub) ubiquitin-like proteins (UBLs) to from cellular is a multifaceted and universal means regulating physiology, controlling the lifetime, localization, activity many critical proteins. Deconjugation Ub UBL performed by class proteases called isopeptidases. Herein described readily quantifiable novel isopeptidase assay platform consisting fused reporter enzyme phospholipase A(2) (PLA(2)). Isopeptidase releases PLA(2), which cleaves its substrate,...
A Streptomyces sp. (NPS008187) isolated from a marine sediment collected in Alaska was found to produce three new pyrrolosesquiterpenes, glyciapyrroles (1), B (2), and C (3), along with the known diketopiperazines cyclo(leucyl-prolyl) (4), cyclo(isoleucyl-prolyl) (5), cyclo(phenylalanyl-prolyl) (6). The structures of 1, 2, 3 were established using spectroscopic methods.
Plinabulin (11, NPI-2358) is a potent microtubule-targeting agent derived from the natural diketopiperazine "phenylahistin" (1) with colchicine-like tubulin depolymerization activity. Compound 11 was recently developed as VDA and now under phase II clinical trials an anticancer drug. To develop more antimicrotubule cytotoxic derivatives based on didehydro-DKP skeleton, we performed further modification tert-butyl or phenyl groups of 11, evaluated their tubulin-binding activities. In SAR...
Abstract Pancreatic ductal adenocarcinoma (PDAC) lethality is due to metastatic dissemination. Characterization of rare, heterogeneous circulating tumor cells (CTCs) can provide insight into metastasis and guide development novel therapies. Using the CTC-iChip purify CTCs from PDAC patients for RNA-seq characterization, we identify three major correlated gene sets, with stemness genes LIN28B/KLF4 , WNT5A LGALS3 enriched in each set; only LIN28B CTC expression was prognostic. CRISPR knockout...
During the course of our screening program designed to discover novel anticancer and anti-infective agents from marine microorganisms, a strain Streptomyces aureoverticillatus (NPS001583) isolated sediment was found produce macrocyclic lactam with cytotoxicity against various tumor cell lines. Using extensive MS, UV, NMR spectral analyses, structure has been established as compound 1, aureoverticillactam, 22-atom incorporating both triene tetraene conjugated olefins.
The reversible conjugation of ubiquitin and ubiquitin-like (UbL) proteins to protein substrates plays a critical role in the regulation many cellular pathways. removal from target is performed by proteases also known as deubiquitylases (DUBs). Owing their substrate specificity central ubiquitylation cell signaling pathways, DUB are attractive targets for therapeutic development. development inhibitors requires assays that amenable high-throughput screening provide rapid assessment inhibitor...
PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression restricted to germ cells attenuation of its activity results in altered meiotic gene transcription, impairment double-stranded breaks pairing between homologous chromosomes. There growing evidence for role aberrant oncogenesis genome instability. Here we report the discovery MRK-740, potent (IC50: 80 ± 16 nM), selective cell-active inhibitor (Chemical Probe). MRK-740 binds...
COVID-19 has resulted in significant morbidity and mortality worldwide. Lateral flow assays can detect anti-Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) antibodies to monitor transmission. However, standardized evaluation of their accuracy tools aid interpreting results are needed.We evaluated 20 IgG IgM selected from available tests April 2020. We the assays' performance using 56 pre-pandemic negative SARS-CoV-2-positive plasma samples, collected 10-40 days after symptom...