المؤلفون: Harnden, Alice C., Davis, Owen A., Box, Gary M., Hayes, Angela, Johnson, Louise D., Henley, Alan T., de Haven Brandon, Alexis K., Valenti, Melanie, Cheung, Kwai-Ming J., Brennan, Alfie, Huckvale, Rosemary, Pierrat, Olivier A., Talbot, Rachel, Bright, Michael D., Akpinar, Hafize Aysin, Miller, Daniel S. J., Tarantino, Dalia, Gowan, Sharon, de Klerk, Selby, McAndrew, Peter Craig, Le Bihan, Yann-Vaï, Meniconi, Mirco, Burke, Rosemary, Kirkin, Vladimir, van Montfort, Rob L. M., Raynaud, Florence I., Rossanese, Olivia W., Bellenie, Benjamin R., Hoelder, Swen

المساهمون: NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research, Cancer Research UK, CRT Pioneer Fund, Sixth Element Capital

المصدر: Journal of Medicinal Chemistry ; volume 66, issue 8, page 5892-5906 ; ISSN 0022-2623 1520-4804

الإتاحة: https://doi.org/10.1021/acs.jmedchem.3c00155Test

المؤلفون: Pasqua, A. Elisa, Sharp, Swee Y., Chessum, Nicola E. A., Hayes, Angela, Pellegrino, Loredana, Tucker, Michael J., Miah, Asadh, Wilding, Birgit, Evans, Lindsay E., Rye, Carl S., Mok, N. Yi, Liu, Manjuan, Henley, Alan T., Gowan, Sharon, De Billy, Emmanuel, te Poele, Robert, Powers, Marissa, Eccles, Suzanne A., Clarke, Paul A., Raynaud, Florence I., Workman, Paul, Jones, Keith, Cheeseman, Matthew D.

المساهمون: Cancer Research UK, Battle Against Cancer Investment Trust, Cancer Research Technology Pioneer Fund

المصدر: Journal of Medicinal Chemistry ; volume 66, issue 8, page 5907-5936 ; ISSN 0022-2623 1520-4804

الإتاحة: https://doi.org/10.1021/acs.jmedchem.3c00156Test

المؤلفون: Huckvale, Rosemary, Harnden, Alice C., Cheung, Kwai-Ming J., Pierrat, Olivier A., Talbot, Rachel, Box, Gary M., Henley, Alan T., de Haven Brandon, Alexis K., Hallsworth, Albert E., Bright, Michael D., Akpinar, Hafize Aysin, Miller, Daniel S. J., Tarantino, Dalia, Gowan, Sharon, Hayes, Angela, Gunnell, Emma A., Brennan, Alfie, Davis, Owen A., Johnson, Louise D., de Klerk, Selby, McAndrew, Craig, Le Bihan, Yann-Vaï, Meniconi, Mirco, Burke, Rosemary, Kirkin, Vladimir, van Montfort, Rob L. M., Raynaud, Florence I., Rossanese, Olivia W., Bellenie, Benjamin R., Hoelder, Swen

المساهمون: Cancer Research UK, Sixth Element Capital

المصدر: Journal of Medicinal Chemistry ; volume 65, issue 12, page 8191-8207 ; ISSN 0022-2623 1520-4804

مصطلحات موضوعية: Drug Discovery, Molecular Medicine

الإتاحة: https://doi.org/10.1021/acs.jmedchem.1c02175Test

المؤلفون: Bellenie, Benjamin R., Cheung, Kwai-Ming J., Varela, Ana, Pierrat, Olivier A., Collie, Gavin W., Box, Gary M., Bright, Michael D., Gowan, Sharon, Hayes, Angela, Rodrigues, Matthew J., Shetty, Kartika N., Carter, Michael, Davis, Owen A., Henley, Alan T., Innocenti, Paolo, Johnson, Louise D., Liu, Manjuan, de Klerk, Selby, Le Bihan, Yann-Vaï, Lloyd, Matthew G., McAndrew, P. Craig, Shehu, Erald, Talbot, Rachel, Woodward, Hannah L., Burke, Rosemary, Kirkin, Vladimir, van Montfort, Rob L. M., Raynaud, Florence I., Rossanese, Olivia W., Hoelder, Swen

المساهمون: Cancer Research UK, European investment fund, Cancer Research Technology

المصدر: Journal of Medicinal Chemistry ; volume 63, issue 8, page 4047-4068 ; ISSN 0022-2623 1520-4804

الإتاحة: https://doi.org/10.1021/acs.jmedchem.9b02076Test

المؤلفون: Read, Martin, Harrison, R. John, Romagnoli, Barbara, Tanious, Farial A., Gowan, Sharon H., Reszka, Anthony P., Wilson, W. David, Kelland, Lloyd R., Neidle, Stephen

المصدر: Proceedings of the National Academy of Sciences of the United States of America, 2001 Apr . 98(9), 4844-4849.

الوصول الحر: https://www.jstor.org/stable/3055526Test

المؤلفون: Andrejeva, Gabriela, Gowan, Sharon, Lin, Gigin, Wong Te Fong, Anne Christine LF, Shamsaei, Elham, Parkes, Harry G., Mui, James, Raynaud, Florence I., Asad, Yasmin, Vizcay-Barrena, Gema, Nikitorowicz-Buniak, Joanna, Valenti, Melanie, Howell, Louise, Fleck, Roland A., Martin, Lesley Ann, Kirkin, Vladimir, Leach, Martin O., Chung, Yuen Li

المصدر: Andrejeva , G , Gowan , S , Lin , G , Wong Te Fong , A C LF , Shamsaei , E , Parkes , H G , Mui , J , Raynaud , F I , Asad , Y , Vizcay-Barrena , G , Nikitorowicz-Buniak , J , Valenti , M , Howell , L , Fleck , R A , Martin , L A , Kirkin , V , Leach , M O & Chung , Y L 2019 , ' De novo phosphatidylcholine synthesis is required for autophagosome membrane formation and maintenance during autophagy ' ....

مصطلحات موضوعية: Autophagosome, autophagy, choline phospholipids, CTP:phosphocholine cytidylyltransferase, phosphatidylcholine, propargylcholine

الوصف: Macroautophagy/autophagy can enable cancer cells to withstand cellular stress and maintain bioenergetic homeostasis by sequestering cellular components into newly formed double-membrane vesicles destined for lysosomal degradation, potentially affecting the efficacy of anti-cancer treatments. Using 13 C-labeled choline and 13 C-magnetic resonance spectroscopy and western blotting, we show increased de novo choline phospholipid (ChoPL) production and activation of PCYT1A (phosphate cytidylyltransferase 1, choline, alpha), the rate-limiting enzyme of phosphatidylcholine (PtdCho) synthesis, during autophagy. We also discovered that the loss of PCYT1A activity results in compromised autophagosome formation and maintenance in autophagic cells. Direct tracing of ChoPLs with fluorescence and immunogold labeling imaging revealed the incorporation of newly synthesized ChoPLs into autophagosomal membranes, endoplasmic reticulum (ER) and mitochondria during anticancer drug-induced autophagy. Significant increase in the colocalization of fluorescence signals from the newly synthesized ChoPLs and mCherry-MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) was also found on autophagosomes accumulating in cells treated with autophagy-modulating compounds. Interestingly, cells undergoing active autophagy had an altered ChoPL profile, with longer and more unsaturated fatty acid/alcohol chains detected. Our data suggest that de novo synthesis may be required to increase autophagosomal ChoPL content and alter its composition, together with replacing phospholipids consumed from other organelles during autophagosome formation and turnover. This addiction to de novo ChoPL synthesis and the critical role of PCYT1A may lead to development of agents targeting autophagy-induced drug resistance. In addition, fluorescence imaging of choline phospholipids could provide a useful way to visualize autophagosomes in cells and tissues. Abbreviations: AKT: AKT serine/threonine kinase; BAX: BCL2 associated X, apoptosis regulator; BECN1: ...

الإتاحة: https://doi.org/10.1080/15548627.2019.1659608Test
https://kclpure.kcl.ac.uk/portal/en/publications/ef637dcb-362c-4fd8-9f92-f838ce4f1d45Test
http://www.scopus.com/inward/record.url?scp=85073817643&partnerID=8YFLogxKTest

المؤلفون: Al-Saffar, Nada M. S., Troy, Helen, Wong Te Fong, Anne-Christine, Paravati, Roberta, Jackson, L. Elizabeth, Gowan, Sharon, Boult, Jessica K. R., Robinson, Simon P., Eccles, Suzanne A., Yap, Timothy A., Leach, Martin O., Chung, Yuen-Li

المصدر: British Journal of Cancer ; volume 119, issue 9, page 1118-1128 ; ISSN 0007-0920 1532-1827

مصطلحات موضوعية: Cancer Research, Oncology

الإتاحة: https://doi.org/10.1038/s41416-018-0242-3Test
http://www.nature.com/articles/s41416-018-0242-3Test
http://www.nature.com/articles/s41416-018-0242-3.pdfTest

المؤلفون: Tucker, Elizabeth R., Tall, Jennifer R., Danielson, Laura S., Gowan, Sharon, Jamin, Yann, Robinson, Simon P., Banerji, Udai, Chesler, Louis

المساهمون: Medical Research Council and SPARKS Clinical Research Training Fellowship, Abbie's Fund, Cancer Research UK Project

المصدر: Molecular Oncology ; volume 11, issue 8, page 996-1006 ; ISSN 1574-7891 1878-0261

الوصف: Targeted inhibition of anaplastic lymphoma kinase ( ALK ) is a successful approach for the treatment of many ALK ‐aberrant malignancies; however, the presence of resistant mutations necessitates both the development of more potent compounds and pharmacodynamic methods with which to determine their efficacy. We describe immunoassays designed to quantitate phosphorylation of ALK , and their use in preclinical models of neuroblastoma, a pediatric malignancy in which gain‐of‐function ALK mutations predict a poor overall outcome to conventional treatment. Validation of the immunoassays is presented using a panel of neuroblastoma cell lines and evidence of on‐target ALK inhibition provided by treatment of a genetically engineered murine model of neuroblastoma with two clinical ALK inhibitors, crizotinib and ceritinib, highlighting the superior efficacy of ceritinib.

الإتاحة: https://doi.org/10.1002/1878-0261.12069Test

المؤلفون: Clarke, Paul A., Ortiz-Ruiz, Maria-Jesus, TePoele, Robert, Adeniji-Popoola, Olajumoke, Box, Gary, Court, Will, Czasch, Stefanie, El Bawab, Samer, Esdar, Christina, Ewan, Ken, Gowan, Sharon, De Haven Brandon, Alexis, Hewitt, Phllip, Hobbs, Stephen M., Kaufmann, Wolfgang, Mallinger, Aurélie, Raynaud, Florence, Roe, Toby, Rohdich, Felix, Schiemann, Kai, Simon, Stephanie, Schneider, Richard, Valenti, Melanie, Weigt, Stefan, Blagg, Julian, Blaukat, Andree, Dale, Trevor C., Eccles, Suzanne A., Hecht, Stefan, Urbahns, Klaus, Workman, Paul, Wienke, Dirk

الوصف: Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it is unclear whether this will impact on the clinical utility of CDK8/19 inhibitors. We discovered two series of potent chemical probes with high selectivity for CDK8/19. Despite pharmacodynamic evidence for robust on-target activity, the compounds exhibited modest, though significant, efficacy against human tumor lines and patient-derived xenografts. Altered gene expression was consistent with CDK8/19 inhibition, including profiles associated with super-enhancers, immune and inflammatory responses and stem cell function. In a mouse model expressing oncogenic beta-catenin, treatment shifted cells within hyperplastic intestinal crypts from a stem cell to a transit amplifying phenotype. In two species, neither probe was tolerated at therapeutically-relevant exposures. The complex nature of the toxicity observed with two structurally-differentiated chemical series is consistent with ontarget effects posing significant challenges to the clinical development of CDK8/19 inhibitors.

وصف الملف: application/pdf

العلاقة: https://orca.cardiff.ac.uk/id/eprint/96966/1/elife-20722-v3.pdfTest; Clarke, Paul A., Ortiz-Ruiz, Maria-Jesus, TePoele, Robert, Adeniji-Popoola, Olajumoke, Box, Gary, Court, Will, Czasch, Stefanie, El Bawab, Samer, Esdar, Christina, Ewan, Ken orcid:0000-0001-6622-9009 orcid:0000-0001-6622-9009, Gowan, Sharon, De Haven Brandon, Alexis, Hewitt, Phllip, Hobbs, Stephen M., Kaufmann, Wolfgang, Mallinger, Aurélie, Raynaud, Florence, Roe, Toby, Rohdich, Felix, Schiemann, Kai, Simon, Stephanie, Schneider, Richard, Valenti, Melanie, Weigt, Stefan, Blagg, Julian, Blaukat, Andree, Dale, Trevor C. https://orca.cardiff.ac.uk/view/cardiffauthors/A050728Q.htmlTest orcid:0000-0002-4880-9963 orcid:0000-0002-4880-9963, Eccles, Suzanne A., Hecht, Stefan, Urbahns, Klaus, Workman, Paul and Wienke, Dirk 2016. Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases. eLife 5 , e20722. 10.7554/eLife.20722 https://doi.org/10.7554/eLife.20722Test file https://orca.cardiff.ac.uk/id/eprint/96966/1/elife-20722-v3.pdfTest

الإتاحة: https://doi.org/10.7554/eLife.20722Test
https://orca.cardiff.ac.uk/id/eprint/96966Test/
https://orca.cardiff.ac.uk/id/eprint/96966/1/elife-20722-v3.pdfTest

المؤلفون: Naseem, Afia, Pal, Akos, Gowan, Sharon, Asad, Yasmin, Donovan, Adam, Temesszentandrási-Ambrus, Csilla, Kis, Emese, Gaborik, Zsuzsanna, Bhalay, Gurdip, Raynaud, Florence

المصدر: Cells (2073-4409); Oct2022, Vol. 11 Issue 20, p3286-N.PAG, 20p

مصطلحات موضوعية: LIQUID chromatography-mass spectrometry, METABOLOMICS, CELL permeability, THYMIDYLATE synthase, METHYLENETETRAHYDROFOLATE reductase

مستخلص: Caco-2 screens are routinely used in laboratories to measure the permeability of compounds and can identify substrates of efflux transporters. In this study, we hypothesized that efflux transporter inhibition of a compound can be predicted by an intracellular metabolic signature in Caco-2 cells in the assay used to test intestinal permeability. Using selective inhibitors and transporter knock-out (KO) cells and a targeted Liquid Chromatography tandem Mass Spectrometry (LC-MS) method, we identified 11 metabolites increased in cells with depleted P-glycoprotein (Pgp) activity. Four metabolites were altered with Breast Cancer Resistance (BCRP) inhibition and nine metabolites were identified in the Multidrug Drug Resistance Protein 2 (MRP2) signature. A scoring system was created that could discriminate among the three transporters and validated with additional inhibitors. Pgp and MRP2 substrates did not score as inhibitors. In contrast, BCRP substrates and inhibitors showed a similar intracellular metabolomic signature. Network analysis of signature metabolites led us to investigate changes of enzymes in one-carbon metabolism (folate and methionine cycles). Our data shows that methylenetetrahydrofolate reductase (MTHFR) protein levels increased with Pgp inhibition and Thymidylate synthase (TS) protein levels were reduced with Pgp and MRP2 inhibition. In addition, the methionine cycle is also affected by both Pgp and MRP2 inhibition. In summary, we demonstrated that the routine Caco-2 assay has the potential to identify efflux transporter inhibitors in parallel with substrates in the assays currently used in many DMPK laboratories and that inhibition of efflux transporters has biological consequences. [ABSTRACT FROM AUTHOR]

: Copyright of Cells (2073-4409) is the property of MDPI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)