A5101865718- Peroxisome Proliferator-Activated Receptors
- Eicosanoids and Hypertension Pharmacology
- Cancer, Hypoxia, and Metabolism
- Cell Image Analysis Techniques
- Viral Infectious Diseases and Gene Expression in Insects
- Fibroblast Growth Factor Research
- Wnt/β-catenin signaling in development and cancer
- Advanced Fluorescence Microscopy Techniques
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- RNA regulation and disease
- Cancer, Lipids, and Metabolism
- Epigenetics and DNA Methylation
- Retinoids in leukemia and cellular processes
- Adenosine and Purinergic Signaling
- Inflammatory mediators and NSAID effects
- Receptor Mechanisms and Signaling
- Cancer-related gene regulation
- Chronic Myeloid Leukemia Treatments
- Pancreatic function and diabetes
- Amino Acid Enzymes and Metabolism
- Protein Kinase Regulation and GTPase Signaling
- Virus-based gene therapy research
- Cell Adhesion Molecules Research
- Antioxidant Activity and Oxidative Stress
- Gestational Diabetes Research and Management
Broad Institute
2017-2023
Amgen (United States)
2012
University of Wisconsin–Madison
2003
Systematic exploration of cancer cell vulnerabilities can inform the development novel therapeutics. Here, through analysis genome-scale loss-of-function datasets, we identify adenosine deaminase acting on RNA (ADAR or ADAR1) as an essential gene for survival a subset lines. ADAR1-dependent lines display increased expression interferon-stimulated genes. Activation type I interferon signaling in context ADAR1 deficiency induce lethality non-ADAR1-dependent ADAR deletion causes activation...
The PPARG gene encoding the nuclear receptor PPARγ is activated in bladder cancer, either directly by amplification or mutation, indirectly mutation of RXRA gene, which encodes heterodimeric partner PPARγ. Here, we show that activating alterations lead to a specific expression signature cancers. Reducing activity, whether pharmacologic inhibition genetic ablation, inhibited proliferation PPARG-activated cancer cells. Our results offer preclinical proof concept for as candidate therapeutic...
Identifying the chemical regulators of biological pathways is a time-consuming bottleneck in developing therapeutics and research compounds. Typically, thousands to millions candidate small molecules are tested target-based biochemical screens or phenotypic cell-based screens, both expensive experiments customized each disease. Here, our uncustomized, virtual, profile-based screening approach instead identifies compounds that match based on information public cell image data, created using...
The ligand-activated nuclear receptor peroxisome-proliferator-activated receptor-γ (PPARG or PPARγ) represents a potential target for new generation of cancer therapeutics, especially in muscle-invasive luminal bladder where PPARγ is critical lineage driver. Here we disclose the discovery series chloro-nitro-arene covalent inverse-agonists that exploit benzoxazole core to improve interactions with corepressors NCOR1 and NCOR2. In vitro treatment sensitive cell lines these compounds results...
Aberrant activation of the Wnt pathway is believed to drive development and growth some cancers. The central role CK1γ in signal transduction makes it an attractive target for treatment Wnt-pathway dependent We describe a structure-based approach that led discovery series pyridyl pyrrolopyridinones as potent selective inhibitors. These compounds exhibited good enzyme cell potency, well selectivity against other CK1 isoforms. A single oral dose compound 13 resulted significant inhibition LRP6...
Abstract Gestational diabetes mellitus (GDM) affects more than 16 million pregnancies annually worldwide and is related to an increased lifetime risk of Type 2 (T2D). The diseases are hypothesized share a genetic predisposition, but there few GWAS studies GDM none them sufficiently powered assess whether any variants or biological pathways specific GDM. We conducted the largest genome-wide association study date in 12,332 cases 131,109 parous female controls FinnGen Study identified 13...
PPAR gamma (PPARG) is a ligand activated transcription factor that regulates genes involved in inflammation, bone biology, lipid homeostasis, as well master regulator of adipogenesis and potential lineage driver luminal bladder cancer. While PPARG agonists lead to transcriptional activation canonical target genes, inverse have the opposite effect through inducing transcriptionally repressive complex leading repression gene expression. many been described tested clinically, offer an...
Abstract Identifying chemical regulators of biological pathways is a time-consuming bottleneck in developing therapeutics and research compounds. Typically, thousands to millions candidate small molecules are tested target-based biochemical screens or phenotypic cell-based screens, both expensive experiments customized each disease. Here, our uncustomized, virtual profile-based screening approach instead identifies compounds that match based on information public cell image data, created...
Abstract A subset of muscle-invasive bladder cancer (BLCA) is typified by PPARG pathway activation. focal gene amplification occurs in 15% patients, and similarly, 5% BLCA patients possess hotspot mutations the requisite heterodimer partner PPARG, RXRA (S427F, S427Y). We used genetic perturbation to study role cancer. Our results show that overexpression mutant alleles activate expression PPARA target genes a ligand-independent manner, cell lines are dependent on for viability. These...
<div>Abstract<p>The <i>PPARG</i> gene encoding the nuclear receptor PPARγ is activated in bladder cancer, either directly by amplification or mutation, indirectly mutation of <i>RXRA</i> gene, which encodes heterodimeric partner PPARγ. Here, we show that activating alterations lead to a specific expression signature cancers. Reducing PPARG activity, whether pharmacologic inhibition genetic ablation, inhibited proliferation PPARG-activated cancer cells. Our...
<p>Supplementary Methods. Supplementary Figure 1. Somatic alterations in PPARG and RXRA are hallmarks of luminal bladder cancer. 2. pathway is activated by overexpression S427F/S427Y, but not other mutant alleles cancer cells. 3. Representation the effects ligand-dependent modulation on interactome. 4. Downregulation FABP4 protein treatment PPARG-activated cell lines inverse-agonist T0070907. 5. Genome engineering scheme for generating reporter line. 6. Basal expression reduced inverse...
<p>Supplementary Methods. Supplementary Figure 1. Somatic alterations in PPARG and RXRA are hallmarks of luminal bladder cancer. 2. pathway is activated by overexpression S427F/S427Y, but not other mutant alleles cancer cells. 3. Representation the effects ligand-dependent modulation on interactome. 4. Downregulation FABP4 protein treatment PPARG-activated cell lines inverse-agonist T0070907. 5. Genome engineering scheme for generating reporter line. 6. Basal expression reduced inverse...
<div>Abstract<p>The <i>PPARG</i> gene encoding the nuclear receptor PPARγ is activated in bladder cancer, either directly by amplification or mutation, indirectly mutation of <i>RXRA</i> gene, which encodes heterodimeric partner PPARγ. Here, we show that activating alterations lead to a specific expression signature cancers. Reducing PPARG activity, whether pharmacologic inhibition genetic ablation, inhibited proliferation PPARG-activated cancer cells. Our...
Abstract PPARG is genomically activated in muscle-invasive bladder cancer through focal gene amplification and hotspot mutations its heterodimer partner, RXRA. However, more than half of the PPARG-activated tumors cell lines do not have identifiable somatic alterations either or Using a PPARG-driven reporter assay RT112 line, we screened probe compounds to identify candidate drivers ligand-independent activation. We found that pan-FGFR inhibitors MEK1/2 antagonized with potency similar...