Benjamin Schwartz
A5035696545- CRISPR and Genetic Engineering
- Renal and related cancers
- Animal Genetics and Reproduction
- DNA Repair Mechanisms
- RNA modifications and cancer
- Cancer-related gene regulation
- Digestive system and related health
- Endoplasmic Reticulum Stress and Disease
- Genomics and Chromatin Dynamics
- Biochemical and Molecular Research
GlaxoSmithKline (United States)
2024-2025
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...
Abstract SLC34A2 is overexpressed in 61% of ovarian cancer and 18% uterine tumors. overexpression believed to be driven by the aberrant activity essential PAX8 transcription factor these Overexpression SLC34A2, a phosphate importer, sensitizes cells genetic depletion XPR1, sole exporter. Importantly, pharmacologic inhibition XPR1 XRBD, peptide molecule that binds extracellular domain 3 (ECL3) antagonize its function, phenocopies lethal impact knockdown on overexpressing cells. This...
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 FANCM (Fanconi anemia, complementation group M) is a human gene that encodes protein plays key role in DNA repair and genome maintenance. Alternative lengthening of telomeres (ALT) mechanism allows cancer cells to maintain telomere length without using telomerase. A synthetic lethal relationship between ALT status levels was uncovered by analyzing CRISPR Screens DepMap database. By telomerase (TERT) as biomarker which negative positive tumors, cell lines TERT or ALT+ were found be...
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 Large scale efforts using CRISPR based gene loss-of-function screens have produced comprehensive catalogs of essentiality in hundreds well annotated cancer models. The equivalent not been generated for gain-of-function. While (LOF) mutations TP53 are frequent cancer, targeting these pharmaceutically remains challenging. To explore synthetic lethalities with p53 LOF we performed genome-wide activation wildtype and knockout isogenic cell lines. We discovered a cluster genes associated...
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 Werner helicase inhibitors (WRNi) are in clinical development for treating patients with microsatellite-unstable (MSI) tumors characterized by defective DNA mismatch repair. Here, we investigate the impact of cancer cell evolutionary adaptation on WRN pharmacological inhibition implications understanding drug selectivity and potential resistance. Coupling genome-wide CRISPR screens gene knockout, no suppressors dependency were identified, underscoring WRN’s essential non-redundant...
<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...