A5056881284- Cancer, Hypoxia, and Metabolism
- Ubiquitin and proteasome pathways
- Ovarian cancer diagnosis and treatment
- Microtubule and mitosis dynamics
- Mitochondrial Function and Pathology
- Cancer-related Molecular Pathways
- Neuroblastoma Research and Treatments
- 14-3-3 protein interactions
- Cancer Treatment and Pharmacology
- Chromatin Remodeling and Cancer
- Carcinogens and Genotoxicity Assessment
- Lung Cancer Research Studies
- Cancer-related gene regulation
- Cancer therapeutics and mechanisms
- Nuclear Receptors and Signaling
- Multiple Myeloma Research and Treatments
- Histone Deacetylase Inhibitors Research
- Pharmaceutical and Antibiotic Environmental Impacts
- Hippo pathway signaling and YAP/TAZ
- Protein Degradation and Inhibitors
- Cellular Mechanics and Interactions
- Chronic Myeloid Leukemia Treatments
- X-ray Diffraction in Crystallography
- Genomics, phytochemicals, and oxidative stress
- Computational Drug Discovery Methods
National Center for Advancing Translational Sciences
2016-2024
Howard Hughes Medical Institute
2023
National Institutes of Health
2016-2023
National Cancer Institute
2023
Center for Cancer Research
2023
United States Military Academy
2002-2013
Merck & Co., Inc., Rahway, NJ, USA (United States)
2010
Deubiquitinases are important components of the protein degradation regulatory network. We report discovery ML364, a small molecule inhibitor deubiquitinase USP2 and its use to interrogate biology putative substrate cyclin D1. ML364 has an IC50 1.1 μm in biochemical assay using internally quenched fluorescent di-ubiquitin substrate. Direct binding was demonstrated microscale thermophoresis. induced increase cellular D1 caused cell cycle arrest as shown Western blottings flow cytometry assays...
Abstract Combination of anti-cancer drugs is broadly seen as way to overcome the often-limited efficacy single agents. The design and testing combinations are however very challenging. Here we present a uniquely large dataset screening over 5000 targeted agent across 81 non-small cell lung cancer lines. Our analysis reveals profound heterogeneity response tumor models. Notably, rarely result in strong gain range observable with Importantly, activity agents more often when co-targeting...
Abstract Colorectal cancers (CRCs) are prevalent worldwide, yet current treatments remain inadequate. Using chemical genetic screens, we identify that co-inhibition of topoisomerase I (TOP1) and NEDD8 is synergistically cytotoxic in human CRC cells. Combination the TOP1 inhibitor irinotecan or its bioactive metabolite SN38 with NEDD8-activating enzyme pevonedistat exhibits synergy patient-derived organoids xenografts. Mechanistically, show blocks ubiquitin/proteasome-dependent repair...
Small cell lung cancer (SCLC) is a recalcitrant malignancy with limited treatment options. Bromodomain and extraterminal domain inhibitors (BETis) have shown promising preclinical activity in SCLC, but the broad sensitivity spectrum limits their clinical prospects. Here, we performed unbiased high-throughput drug combination screens to identify therapeutics that could augment antitumor activities of BETis SCLC. We found multiple drugs targeting PI-3K–AKT–mTOR pathway synergize BETis, among...
Abstract Current treatment options for metastatic adrenocortical carcinoma (ACC) have limited efficacy, despite the common use of mitotane and cytotoxic agents. This study aimed to identify novel therapeutic ACC. An extensive drug screen was conducted compounds with potential activity against ACC cell lines. We further investigated mechanism action identified compound, TAK-243, its synergistic effects current therapeutics, efficacy in models including patient-derived organoids mouse...
Oncogenic RAS mutations are common in multiple myeloma (MM), an incurable malignancy of plasma cells. However, the mechanisms pathogenic signaling this disease remain enigmatic and difficult to inhibit therapeutically. We employ unbiased proteogenomic approach dissect MM. discover that mutant isoforms organize a complex with amino acid transporter, SLC3A2, MTOR on endolysosomes, which directly activates mTORC1 by co-opting sensing pathways. MM tumors high expression mTORC1-dependent genes...
3-Methylindole (3MI), melatonin (Mel), serotonin (Ser), and tryptamine (Tryp) were evaluated in vitro for their potential to induce DNA adducts, strand breaks, chromosomal aberrations (Abs), inhibition of synthesis, mutations. All compounds produced adducts calf thymus the presence rat liver S9. In cultured hepatocytes, all but none induced breaks. Chinese hamster ovary cells, 3MI Mel Abs, synthesis with without S9, except that S9 did not form adducts. Ser formed was an equivocal Abs...
<p>Cytotoxicity of TAK-243 on ACC cell lines. <b>A,</b> Concentration–response curve and IC<sub>50</sub> values in lines SW-13. Cell viability after 72 hours under the indicated drug concentrations was measured by CellTiter-Glo assay. <b>B,</b> Expression ABC transporters (MDR-1, BCRP) SLFN11 Proteins were extracted from each line expression SLFN11, MDR-1, BCRP evaluated Western blotting. <b>C,</b> Effects DNA synthesis cycle. CU-ACC1,...
<div>Abstract<p>Current treatment options for metastatic adrenocortical carcinoma (ACC) have limited efficacy, despite the common use of mitotane and cytotoxic agents. This study aimed to identify novel therapeutic ACC. An extensive drug screen was conducted compounds with potential activity against ACC cell lines. We further investigated mechanism action identified compound, TAK-243, its synergistic effects current therapeutics, efficacy in models including patient-derived...
<p>NCATS screening identifies TAK-243 as one of the most potent drugs against ACC cell lines. <b>A,</b> CU-ACC1, CU-ACC2, and NCI-H295R lines were screened with NCATS MIPE v5.0 (MIPE 5.0) library approved investigational (<i>n</i> = 2,480). Drugs Z-AUC values less than −1.5 good-quality dose–response curves selected. The number effective in three is shown Venn diagram (left). 21 commonly their mechanism action tabulated. <b>B,</b> arranged order for...
<p>Expression of ABCB1/SLFN11 and BCL2/BAX in clinical cancer samples.</p>
<p>Immunostaining of CU-ACC1 xenograft tissue. Body weight changes in mice.</p>
<p>Synergistic effect of TAK-243 on Navitoclax. Analysis synergistic effects using the MTT assay.</p>
<p>Synergistic effect of TAK-243 on Navitoclax. Analysis synergistic effects using the MTT assay.</p>
<p>High UBA1 expression, and hyperactivation of the E1 E2 enzymes ubiquitin pathways in ACC.</p>
<p>Immunostaining of CU-ACC1 xenograft tissue. Body weight changes in mice.</p>
<p>Expression of ABCB1/SLFN11 and BCL2/BAX in clinical cancer samples.</p>
<p>High UBA1 expression, and hyperactivation of the E1 E2 enzymes ubiquitin pathways in ACC.</p>