A5004826557- CRISPR and Genetic Engineering
- Renal and related cancers
- DNA Repair Mechanisms
- Animal Genetics and Reproduction
- RNA modifications and cancer
- Digestive system and related health
- Epigenetics and DNA Methylation
- Cancer-related gene regulation
- Virus-based gene therapy research
- Cancer, Hypoxia, and Metabolism
- Ubiquitin and proteasome pathways
- Chromatin Remodeling and Cancer
- Cancer-related Molecular Pathways
- Neurogenetic and Muscular Disorders Research
- Genomics and Chromatin Dynamics
- Endoplasmic Reticulum Stress and Disease
- Peptidase Inhibition and Analysis
- Biochemical and Molecular Research
- Biomedical Ethics and Regulation
- Neurofibromatosis and Schwannoma Cases
- Health, Environment, Cognitive Aging
- Molecular Biology Techniques and Applications
GlaxoSmithKline (United States)
2023-2025
Providence College
2024-2025
The University of Texas MD Anderson Cancer Center
2024
Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due expanded DNA (TA)n dinucleotide repeats. is a promising synthetic lethal target for MSI tumors, and inhibitors are in development. In this study, we used CRISPR-Cas9 base editing map residues critical cells, validating the domain as primary drug target. Fragment-based screening led development of potent highly selective covalent inhibitors. These compounds selectively suppressed model growth vitro...
Large-scale genome-wide CRISPR screens have identified WRN helicase, RecQ family, as a promising synthetic lethal target for microsatellite instability-high (MSI-H) cancers across tumor types. GSK4418959 (IDE275) was discovered novel helicase inhibitor to treat MSI-H cancer. Here, we present the cellular and in vivo evidence demonstrate selectivity efficacy of multiple models various solid types, including colorectal (CRC), endometrial, gastric cancers. demonstrates potent anti-proliferative...
Recent large-scale genome wide CRISPR screens identified Werner (WRN) Helicase as uniquely essential to cell survival specifically in the microsatellite instability-high (MSI-H) cancer setting. This synthetic lethal relationship elevated WRN an attractive precision therapeutic target for treatment of MSI-H cancers, irrespective tumor type. High-throughput screening a hit characterized by low potency inhibition ATPase function. poster describes systematic optimization this resulting discovery...
Abstract GSK4418959 (IDE275) is a clinical-stage WRN helicase inhibitor designed to treat MSI-H cancer. This compound phenocopies genetic inactivation, with exquisite selectivity in large panel of cell lines. Results from extensive line profiling indicate strong correlation between MSI score and sensitivity the compound. Interestingly, also correlates TA-repeat prevalence individual There appears be no bias toward specific mutations dMMR panel, compound's not affected by driver mutation...
Abstract During protein translation, ribosomes may stall for a number of reasons including the presence mRNA defects, cell stress, nonoptimal codon clusters, ribosome collisions, etc. One mechanism resolving these stalled is to extract using SKI complex. Focadhesin (FOCAD) provides an essential function complex by stabilizing and protecting proteins from degradation, but it also common collateral deletion with CDKN2A- MTAP-loss in many cancers. In absence functional complex, are resolved via...
Abstract Large scale genome wide CRISPR screens identified WRN helicase as a promising synthetic lethal target for MSI-H cancers, independent of tumor type. Here we describe the discovery novel clinical inhibitor GSK4418959 (IDE275), which recapitulates lethality genetic inhibition in vitro and vivo. (IDE275) engages unique allosteric site domain, competing with ATP binding inducing an inhibitory conformation distinct from previously reported inhibitors. It selectively inhibits ATPase DNA...
Abstract Werner syndrome protein (WRN) is a RecQ-family helicase involved in the maintenance of genome integrity. Germline mutations WRN cause premature aging and cancer predisposition. Analysis systematic RNAi CRISPR screening data has previously revealed that essential for survival cell lines with high microsatellite instability (MSI-H). We have developed potent selective small-molecule inhibitors (WRNi) showed pharmacological inhibition causes lethality induction DNA damage markers...
Abstract Microsatellite-unstable (MSI) cancers depend on the WRN helicase to resolve replication stress from expanded (TA)-dinucleotide repeats. is a promising synthetic lethal target for MSI tumours and inhibitors are being developed. Here, we used CRISPR-Cas9 base editing map residues critical lethality, validating domain as primary guiding inhibitor discovery. Fragment-based screening led discovery of potent highly selective covalent same chemical series. These compounds strikingly...
<p>Supplementary Figure 1. Generating base editor-expressing MSI cell lines for screening. Supplementary 2. Quality control base-editor screens in lines. 3. Discovery and characterization of novel inhibitors WRN helicase. 4. Correlation inhibitor sensitivity with genetic molecular markers models. 5. Comparative analysis DNA damage MSS cells treated inactivation. 6: Effects GSK_WRN4 on colorectal cancer xenografts.</p>
<p>This table lists the results from Base editing screen</p>
<p>This file contains details of the BE sgRNA library</p>
<p>This file contain information on the Cell lines and organoids used in this study</p>
<div>Abstract<p>Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due expanded DNA (TA)<sub>n</sub> dinucleotide repeats. is a promising synthetic lethal target for MSI tumors, and inhibitors are in development. In this study, we used CRISPR–Cas9 base editing map residues critical cells, validating the domain as primary drug target. Fragment-based screening led development of potent highly selective covalent inhibitors. These...
<p>Supplementary Figure 1. Generating base editor-expressing MSI cell lines for screening. Supplementary 2. Quality control base-editor screens in lines. 3. Discovery and characterization of novel inhibitors WRN helicase. 4. Correlation inhibitor sensitivity with genetic molecular markers models. 5. Comparative analysis DNA damage MSS cells treated inactivation. 6: Effects GSK_WRN4 on colorectal cancer xenografts.</p>
<p>This file contain information on the Cell lines and organoids used in this study</p>
<p>This table lists the results from Base editing screen</p>
<p>This file contains details of the BE sgRNA library</p>
<div>Abstract<p>Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due expanded DNA (TA)<sub>n</sub> dinucleotide repeats. is a promising synthetic lethal target for MSI tumors, and inhibitors are in development. In this study, we used CRISPR–Cas9 base editing map residues critical cells, validating the domain as primary drug target. Fragment-based screening led development of potent highly selective covalent inhibitors. These...
Abstract Studies presented here were conducted to validate UXS1 as a synthetic lethal target in UGDHhigh expressing cancer. In vitro and vivo knockout studies used investigate the role of UGDH-high cancers. has been validated cancer cell lines highly UGDH by CRISPR-mediated panel lung lines. addition expression predicting dependency, we have shown overexpression functional drives such that rescues cellular growth defects seen with UXS1-knockout alone. Furthermore, catalytic activity was be...