Browsing ICR Divisions by author "Raynaud, Florence"
Now showing items 21-40 of 66
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Differences in Signaling Patterns on PI3K Inhibition Reveal Context Specificity in KRAS-Mutant Cancers.
Stewart, A; Coker, EA; Pölsterl, S; Georgiou, A; Minchom, AR; et al. (AMER ASSOC CANCER RESEARCH, 2019-08-01)It is increasingly appreciated that drug response to different cancers driven by the same oncogene is different and may relate to differences in rewiring of signal transduction. We aimed to study differences in dynamic ... -
Discovering cell-active BCL6 inhibitors: effectively combining biochemical HTS with multiple biophysical techniques, X-ray crystallography and cell-based assays.
Pierrat, OA; Liu, M; Collie, GW; Shetty, K; Rodrigues, MJ; et al. (NATURE PORTFOLIO, 2022-11-03)By suppressing gene transcription through the recruitment of corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls a transcriptional network required for the formation and maintenance of B-cell germinal centres. ... -
Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9.
Rye, CS; Chessum, NEA; Lamont, S; Pike, KG; Faulder, P; et al. (ROYAL SOC CHEMISTRY, 2016-08-01)Heat shock factor 1 (HSF1) is a transcription factor that plays key roles in cancer, including providing a mechanism for cell survival under proteotoxic stress. Therefore, inhibition of the HSF1-stress pathway represents ... -
Discovery of a Chemical Probe Bisamide (CCT251236): An Orally Bioavailable Efficacious Pirin Ligand from a Heat Shock Transcription Factor 1 (HSF1) Phenotypic Screen.
Cheeseman, MD; Chessum, NEA; Rye, CS; Pasqua, AE; Tucker, MJ; et al. (AMER CHEMICAL SOC, 2017-01-12)Phenotypic screens, which focus on measuring and quantifying discrete cellular changes rather than affinity for individual recombinant proteins, have recently attracted renewed interest as an efficient strategy for drug ... -
Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones.
Harnden, AC; Davis, OA; Box, GM; Hayes, A; Johnson, LD; et al. (AMER CHEMICAL SOC, 2023-04-27)B-cell lymphoma 6 (BCL6) is a transcriptional repressor and oncogenic driver of diffuse large B-cell lymphoma (DLBCL). Here, we report the optimization of our previously reported tricyclic quinolinone series for the ... -
Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen.
Mallinger, A; Crumpler, S; Pichowicz, M; Waalboer, D; Stubbs, M; et al. (AMER CHEMICAL SOC, 2015-02-26)WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted ... -
Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19.
Mallinger, A; Schiemann, K; Rink, C; Stieber, F; Calderini, M; et al. (AMER CHEMICAL SOC, 2016-02-11)The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 ... -
Dual blockade of the PI3K/AKT/mTOR (AZD8055) and RAS/MEK/ERK (AZD6244) pathways synergistically inhibits rhabdomyosarcoma cell growth in vitro and in vivo.
Renshaw, J; Taylor, KR; Bishop, R; Valenti, M; De Haven Brandon, A; et al. (AMER ASSOC CANCER RESEARCH, 2013-08-05)PURPOSE: To provide rationale for using phosphoinositide 3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathway inhibitors to treat rhabdomyosarcomas, a major cause of pediatric and adolescent cancer deaths. ... -
Effect of acute total sleep deprivation on plasma melatonin, cortisol and metabolite rhythms in females.
Honma, A; Revell, VL; Gunn, PJ; Davies, SK; Middleton, B; et al. (WILEY, 2020-01-01)Disruption to sleep and circadian rhythms can impact on metabolism. The study aimed to investigate the effect of acute sleep deprivation on plasma melatonin, cortisol and metabolites, to increase understanding of the ... -
Erratum to: investigation of metabolites for estimating blood deposition time.
Lech, K; Liu, F; Davies, SK; Ackermann, K; Ang, JE; et al. (2018-01) -
FGF7-FGFR2 autocrine signaling increases growth and chemoresistance of fusion-positive rhabdomyosarcomas.
Milton, CI; Selfe, J; Aladowicz, E; Man, SYK; Bernauer, C; et al. (WILEY, 2021-11-30)Rhabdomyosarcomas are aggressive pediatric soft-tissue sarcomas and include high-risk PAX3-FOXO1 fusion-gene-positive cases. Fibroblast growth factor receptor 4 (FGFR4) is known to contribute to rhabdomyosarcoma progression; ... -
First-in-Human Study of AT13148, a Dual ROCK-AKT Inhibitor in Patients with Solid Tumors.
McLeod, R; Kumar, R; Papadatos-Pastos, D; Mateo, J; Brown, JS; et al. (AMER ASSOC CANCER RESEARCH, 2020-09-15)PURPOSE: AT13148 is an oral AGC kinase inhibitor, which potently inhibits ROCK and AKT kinases. In preclinical models, AT13148 has been shown to have antimetastatic and antiproliferative activity. PATIENTS AND METHODS: The ... -
High Proliferation Rate and a Compromised Spindle Assembly Checkpoint Confers Sensitivity to the MPS1 Inhibitor BOS172722 in Triple-Negative Breast Cancers.
Anderhub, SJ; Mak, GW-Y; Gurden, MD; Faisal, A; Drosopoulos, K; et al. (AMER ASSOC CANCER RESEARCH, 2019-10-01)BOS172722 (CCT289346) is a highly potent, selective, and orally bioavailable inhibitor of spindle assembly checkpoint kinase MPS1. BOS172722 treatment alone induces significant sensitization to death, particularly in highly ... -
HSF1 Pathway Inhibitor Clinical Candidate (CCT361814/NXP800) Developed from a Phenotypic Screen as a Potential Treatment for Refractory Ovarian Cancer and Other Malignancies.
Pasqua, AE; Sharp, SY; Chessum, NEA; Hayes, A; Pellegrino, L; et al. (AMER CHEMICAL SOC, 2023-04-27)CCT251236 1, a potent chemical probe, was previously developed from a cell-based phenotypic high-throughput screen (HTS) to discover inhibitors of transcription mediated by HSF1, a transcription factor that supports ... -
Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo.
Huckvale, R; Harnden, AC; Cheung, K-MJ; Pierrat, OA; Talbot, R; et al. (AMER CHEMICAL SOC, 2022-06-23)The transcriptional repressor BCL6 is an oncogenic driver found to be deregulated in lymphoid malignancies. Herein, we report the optimization of our previously reported benzimidazolone molecular glue-type degrader CCT369260 ... -
Individualized Prediction of Drug Response and Rational Combination Therapy in NSCLC Using Artificial Intelligence-Enabled Studies of Acute Phosphoproteomic Changes.
Coker, EA; Stewart, A; Ozer, B; Minchom, A; Pickard, L; et al. (AMER ASSOC CANCER RESEARCH, 2022-06-01)We hypothesize that the study of acute protein perturbation in signal transduction by targeted anticancer drugs can predict drug sensitivity of these agents used as single agents and rational combination therapy. We assayed ... -
Inhibition of mTOR-kinase destabilizes MYCN and is a potential therapy for MYCN-dependent tumors.
Vaughan, L; Clarke, PA; Barker, K; Chanthery, Y; Gustafson, CW; et al. (IMPACT JOURNALS LLC, 2016-09-06)MYC oncoproteins deliver a potent oncogenic stimulus in several human cancers, making them major targets for drug development, but efforts to deliver clinically practical therapeutics have not yet been realized. In childhood ... -
Interlaboratory Reproducibility of a Targeted Metabolomics Platform for Analysis of Human Serum and Plasma.
Siskos, AP; Jain, P; Römisch-Margl, W; Bennett, M; Achaintre, D; et al. (AMER CHEMICAL SOC, 2017-01-03)A critical question facing the field of metabolomics is whether data obtained from different centers can be effectively compared and combined. An important aspect of this is the interlaboratory precision (reproducibility) ... -
Into Deep Water: Optimizing BCL6 Inhibitors by Growing into a Solvated Pocket.
Lloyd, MG; Huckvale, R; Cheung, K-MJ; Rodrigues, MJ; Collie, GW; et al. (AMER CHEMICAL SOC, 2021-12-09)We describe the optimization of modestly active starting points to potent inhibitors of BCL6 by growing into a subpocket, which was occupied by a network of five stably bound water molecules. Identifying potent inhibitors ... -
Intracellular Metabolomics Identifies Efflux Transporter Inhibitors in a Routine Caco-2 Cell Permeability Assay-Biological Implications.
Naseem, A; Pal, A; Gowan, S; Asad, Y; Donovan, A; et al. (MDPI, 2022-10-19)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 ...