Browsing by author "Workman, Paul"
Now showing items 41-60 of 63
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Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma.
Poon, E; Liang, T; Jamin, Y; Walz, S; Kwok, C; et al. (AMER SOC CLINICAL INVESTIGATION INC, 2020-11-02)The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show ... -
Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control.
Pawlyn, C; Bright, MD; Buros, AF; Stein, CK; Walters, Z; et al. (SPRINGERNATURE, 2017-03-31)Myeloma is heterogeneous at the molecular level with subgroups of patients characterised by features of epigenetic dysregulation. Outcomes for myeloma patients have improved over the past few decades except for molecularly ... -
Patient-derived organoids model treatment response of metastatic gastrointestinal cancers.
Vlachogiannis, G; Hedayat, S; Vatsiou, A; Jamin, Y; Fernández-Mateos, J; et al. (AMER ASSOC ADVANCEMENT SCIENCE, 2018-02-23)Patient-derived organoids (PDOs) have recently emerged as robust preclinical models; however, their potential to predict clinical outcomes in patients has remained unclear. We report on a living biobank of PDOs from ... -
Pediatric and adult glioblastoma radiosensitization induced by PI3K/mTOR inhibition causes early metabolic alterations detected by nuclear magnetic resonance spectroscopy.
Agliano, A; Balarajah, G; Ciobota, DM; Sidhu, J; Clarke, PA; et al. (IMPACT JOURNALS LLC, 2017-07-18)Poor outcome for patients with glioblastomas is often associated with radioresistance. PI3K/mTOR pathway deregulation has been correlated with radioresistance; therefore, PI3K/mTOR inhibition could render tumors radiosensitive. ... -
Pharmacodynamic and Clinical Results from a Phase I/II Study of the HSP90 Inhibitor Onalespib in Combination with Abiraterone Acetate in Prostate Cancer.
Slovin, S; Hussain, S; Saad, F; Garcia, J; Picus, J; et al. (AMER ASSOC CANCER RESEARCH, 2019-08-01)PURPOSE: Onalespib is a potent, fragment-derived second-generation HSP90 inhibitor with preclinical activity in castration-resistant prostate cancer (CPRC) models. This phase I/II trial evaluated onalespib in combination ... -
Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation.
Ang, JE; Pandher, R; Ang, JC; Asad, YJ; Henley, AT; et al. (AMER ASSOC CANCER RESEARCH, 2016-06-01)PI3K plays a key role in cellular metabolism and cancer. Using a mass spectrometry-based metabolomics platform, we discovered that plasma concentrations of 26 metabolites, including amino acids, acylcarnitines, and ... -
Polypharmacology in Precision Oncology: Current Applications and Future Prospects.
Antolin, AA; Workman, P; Mestres, J; Al-Lazikani, B (BENTHAM SCIENCE PUBL LTD, 2017-01-24)Over the past decade, a more comprehensive, large-scale approach to studying cancer genetics and biology has revealed the challenges of tumor heterogeneity, adaption, evolution and drug resistance, while systems-based ... -
Privileged Structures and Polypharmacology within and between Protein Families.
Meyers, J; Chessum, NEA; Ali, S; Mok, NY; Wilding, B; et al. (AMER CHEMICAL SOC, 2018-12-13)Polypharmacology is often a key contributor to the efficacy of a drug, but is also a potential risk. We investigated two hits discovered via a cell-based phenotypic screen, the CDK9 inhibitor CCT250006 (1) and the pirin ... -
Public resources for chemical probes: the journey so far and the road ahead.
Antolin, AA; Workman, P; Al-Lazikani, B (Future Science Ltd, 2019-11-28)High-quality small molecule chemical probes are extremely valuable for biological research and target validation. However, frequent use of flawed small-molecule inhibitors produces misleading results and diminishes the ... -
Restricting direct interaction of CDC37 with HSP90 does not compromise chaperoning of client proteins.
Smith, JR; de Billy, E; Hobbs, S; Powers, M; Prodromou, C; et al. (NATURE PUBLISHING GROUP, 2015-01-02)The HSP90 molecular chaperone plays a key role in the maturation, stability and activation of its clients, including many oncogenic proteins. Kinases are a substantial and important subset of clients requiring the key ... -
RNAi screen reveals synthetic lethality between cyclin G-associated kinase and FBXW7 by inducing aberrant mitoses.
Dolly, SO; Gurden, MD; Drosopoulos, K; Clarke, P; de Bono, J; et al. (NATURE PUBLISHING GROUP, 2017-09-26)BACKGROUND: F-box and WD40 repeat domain-containing 7 (FBXW7) is an E3 ubiquitin ligase involved in the ubiquitination and degradation of multiple oncogenic substrates. The tumour suppressor function is frequently lost in ... -
Second-Generation HSP90 Inhibitor Onalespib Blocks mRNA Splicing of Androgen Receptor Variant 7 in Prostate Cancer Cells.
Ferraldeschi, R; Welti, J; Powers, MV; Yuan, W; Smyth, T; et al. (AMER ASSOC CANCER RESEARCH, 2016-05-01)Resistance to available hormone therapies in prostate cancer has been associated with alternative splicing of androgen receptor (AR) and specifically, the expression of truncated and constitutively active AR variant 7 ... -
Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets.
Wedge, DC; Gundem, G; Mitchell, T; Woodcock, DJ; Martincorena, I; et al. (NATURE PUBLISHING GROUP, 2018-05-01)Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer ... -
Signalling involving MET and FAK supports cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases.
Zhang, C; Stockwell, SR; Elbanna, M; Ketteler, R; Freeman, J; et al. (NATURE PUBLISHING GROUP, 2019-07-25)Deregulation of cyclin-dependent kinases 4 and 6 (CDK4/6) is highly prevalent in cancer; yet, inhibitors against these kinases are currently used only in restricted tumour contexts. The extent to which cancers depend on ... -
SiGNet: A signaling network data simulator to enable signaling network inference.
Coker, EA; Mitsopoulos, C; Workman, P; Al-Lazikani, B (PUBLIC LIBRARY SCIENCE, 2017-05-17)Network models are widely used to describe complex signaling systems. Cellular wiring varies in different cellular contexts and numerous inference techniques have been developed to infer the structure of a network from ... -
Solution structure of the Hop TPR2A domain and investigation of target druggability by NMR, biochemical and in silico approaches.
Darby, JF; Vidler, LR; Simpson, PJ; Al-Lazikani, B; Matthews, SJ; et al. (NATURE PORTFOLIO, 2020-09-29)Heat shock protein 90 (Hsp90) is a molecular chaperone that plays an important role in tumour biology by promoting the stabilisation and activity of oncogenic 'client' proteins. Inhibition of Hsp90 by small-molecule drugs, ... -
Structural and functional characterisation of human RNA helicase DHX8 provides insights into the mechanism of RNA-stimulated ADP release.
Felisberto-Rodrigues, C; Thomas, JC; McAndrew, C; Le Bihan, Y-V; Burke, R; et al. (PORTLAND PRESS LTD, 2019-09-13)DHX8 is a crucial DEAH-box RNA helicase involved in splicing and required for the release of mature mRNA from the spliceosome. Here, we report the biochemical characterisation of full-length human DHX8 and the catalytically ... -
Structure-based drug design: aiming for a perfect fit.
van Montfort, RLM; Workman, P (PORTLAND PRESS LTD, 2017-11-08)Knowledge of the three-dimensional structure of therapeutically relevant targets has informed drug discovery since the first protein structures were determined using X-ray crystallography in the 1950s and 1960s. In this ... -
The BRAF Inhibitor Vemurafenib Activates Mitochondrial Metabolism and Inhibits Hyperpolarized Pyruvate-Lactate Exchange in BRAF-Mutant Human Melanoma Cells.
Delgado-Goni, T; Miniotis, MF; Wantuch, S; Parkes, HG; Marais, R; et al. (AMER ASSOC CANCER RESEARCH, 2016-12-01)Understanding the impact of BRAF signaling inhibition in human melanoma on key disease mechanisms is important for developing biomarkers of therapeutic response and combination strategies to improve long-term disease ... -
The Chemical Probes Portal: an expert review-based public resource to empower chemical probe assessment, selection and use.
Antolin, AA; Sanfelice, D; Crisp, A; Villasclaras Fernandez, E; Mica, IL; et al. (OXFORD UNIV PRESS, 2023-01-06)We describe the Chemical Probes Portal (https://www.chemicalprobes.org/), an expert review-based public resource to empower chemical probe assessment, selection and use. Chemical probes are high-quality small-molecule ...