Angham Al Saedi
A5008030158- CRISPR and Genetic Engineering
- Renal and related cancers
- Animal Genetics and Reproduction
- RNA modifications and cancer
- DNA Repair Mechanisms
- Digestive system and related health
- Cancer-related gene regulation
- Cancer-related Molecular Pathways
- Virus-based gene therapy research
- Genomics and Chromatin Dynamics
- Biochemical and Molecular Research
- Genetic factors in colorectal cancer
- Endoplasmic Reticulum Stress and Disease
Wellcome Sanger Institute
2023-2024
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...
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...
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...
Abstract 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 tumours, and inhibitors are in development. Here, 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 In...
<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 Microsatellite instability (MSI) is caused by deficient DNA mismatch repair (MMR) and a ubiquitous feature of cancer. Werner syndrome (WRN) helicase involved in genome stability repair. We identified WRN as synthetic-lethal target dMMR/MSI cancers highlighted inhibition therapeutic option for refractory to available therapies. A previously unappreciated genetic cancer cells, (TA)n-dinucleotide repeat expansions, were recently reported cause vulnerability depletion. Our mechanistic...