Here, we provide a detailed protocol for synthetic lethality screens in a Jurkat T cell leukemia line using cell death as the readout measuring the combinatorial effect of a pan-PI3K inhibitor (GDC0941) with specific gene depletion by shRNA. We describe the use of an ultra-complex shRNA library, coverage considerations, time frames, protocol details, and bottlenecks with images to facilitate similar approaches. We discuss how this protocol resource can be readily adapted by investigators. For complete details on the use and execution of this protocol, please refer to (Mues et al., 2019).
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http://dx.doi.org/10.1016/j.xpro.2020.100016 | DOI Listing |
J Med Chem
January 2025
Medicinal Chemistry Department, Shanghai Haiyan Pharmaceutical Technology Co., Ltd., Pudong New Area, Shanghai 201203, China.
Synthetic lethality offers a robust strategy for discovering the next generation of precision medicine therapies tailored for molecularly defined patient populations. MAT2A inhibition is synthetically lethal in several cancers that exhibit a homozygous deletion of -methyl-5'-thioadenosine phosphorylase (MTAP). Herein, we report the identification of novel MAT2A inhibitors featuring a spiral ring to circumvent the C-N atropisomeric chirality utilizing structure-based drug design.
View Article and Find Full Text PDFAdv Exp Med Biol
January 2025
Cancer Research UK Scotland Centre (Edinburgh), Institute of Genetics & Cancer, University of Edinburgh, Edinburgh, UK.
E-cadherin is a transmembrane protein and central component of adherens junctions (AJs). The extracellular domain of E-cadherin forms homotypic interactions with E-cadherin on adjacent cells, facilitating the formation of cell-cell adhesions, known as AJs, between neighbouring cells. The intracellular domain of E-cadherin interacts with α-, β- and p120-catenins, linking the AJs to the actin cytoskeleton.
View Article and Find Full Text PDFCell Prolif
January 2025
NewStem LTD, Jerusalem, Israel.
Synthetic lethality is defined as a type of genetic interaction where the combination of two genetic events results in cell death, whereas each of them separately does not. Synthetic lethality can be a useful tool in personalised oncology. MLH1 is a cancer-related gene that has a central role in DNA mismatch-repair and TP53 is the most frequently mutated gene in cancer.
View Article and Find Full Text PDFBraz J Microbiol
January 2025
Department of Postgraduate Program in Animal Science, University of Franca (UNIFRAN), Av. Dr. Armando Salles Oliveira, 201, Parque Universitário, Franca, SP, CEP 14.404-600, Brazil.
Failures in endodontic treatments are common due to microbial resistance in the pulp canal. The study evaluated the in vitro activity of polyhexamethylene guanidine hydrochloride (PHMGH) against endodontic strains, as well as in vivo toxicity. Using minimum inhibitory concentration and minimum bactericidal concentration techniques, PHMGH was effective against all microorganisms, even at low concentrations.
View Article and Find Full Text PDFActa Pharm Sin B
December 2024
Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China.
encodes a DNA methyltransferase involved in development, cell differentiation, and gene transcription, which is mutated and aberrant-expressed in cancers. Here, we revealed that loss of promotes malignant phenotypes in lung cancer. Based on the epigenetic inhibitor library synthetic lethal screening, we found that small-molecule HDAC6 inhibitors selectively killed -defective NSCLC cells.
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