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1. Quizartinib-resistant FLT3-ITD acute myeloid leukemia cells are sensitive to the FLT3-Aurora kinase inhibitor CCT241736

Author

Moore, Andrew S., Faisal, Amir, Mak, Grace W.Y., Miraki-Moud, Farideh, Bavetsias, Vassilios, Valenti, Melanie, Box, Gary, Hallsworth, Albert, de Haven Brandon, Alexis, Xavier, Cristina P.R., Stronge, Randal, Pearson, Andrew D.J., Blagg, Julian, Raynaud, Florence I., Chopra, Rajesh, Eccles, Suzanne A., Taussig, David C., and Linardopoulos, Spiros

Published
2020
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3. Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer

Author

Wagner, Steve, Vlachogiannis, Georgios, De Haven Brandon, Alexis, Valenti, Melanie, Box, Gary, Jenkins, Liam, Mancusi, Caterina, Self, Annette, Manodoro, Floriana, Assiotis, Ioannis, Robinson, Penny, Chauhan, Ritika, Rust, Alistair G., Matthews, Nik, Eason, Kate, Khan, Khurum, Starling, Naureen, Cunningham, David, Sadanandam, Anguraj, Isacke, Clare M., Kirkin, Vladimir, Valeri, Nicola, and Whittaker, Steven R.

Published
2019
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7. Correction: Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer

Author

Wagner, Steve, Vlachogiannis, Georgios, De Haven Brandon, Alexis, Valenti, Melanie, Box, Gary, Jenkins, Liam, Mancusi, Caterina, Self, Annette, Manodoro, Floriana, Assiotis, Ioannis, Robinson, Penny, Chauhan, Ritika, Rust, Alistair G., Matthews, Nik, Eason, Kate, Khan, Khurum, Starling, Naureen, Cunningham, David, Sadanandam, Anguraj, Isacke, Clare M., Kirkin, Vladimir, Valeri, Nicola, and Whittaker, Steven R.

Published
2019
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8. Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer

Author

Wagner, Steve, Vlachogiannis, Georgios, De Haven Brandon, Alexis, Valenti, Melanie, Box, Gary, Jenkins, Liam, Mancusi, Caterina, Self, Annette, Manodoro, Floriana, Assiotis, Ioannis, Robinson, Penny, Chauhan, Ritika, Rust, Alistair G., Matthews, Nik, Eason, Kate, Khan, Khurum, Starling, Naureen, Cunningham, David, Sadanandam, Anguraj, Isacke, Clare M., Kirkin, Vladimir, Valeri, Nicola, and Whittaker, Steven R.

Subjects
Pyridones, Correction, Drug Synergism, Azepines, Pyrimidinones, Triazoles, Xenograft Model Antitumor Assays, Colorectal cancer, Article, Gene Expression Regulation, Neoplastic, Organoids, Proto-Oncogene Proteins p21(ras), Mice, Drug Resistance, Neoplasm, Cell Line, Tumor, Mutation, Cancer genomics, Animals, Humans, Female, Gene Regulatory Networks, Interferons, Colorectal Neoplasms
Abstract

Despite showing clinical activity in BRAF-mutant melanoma, the MEK inhibitor (MEKi) trametinib has failed to show clinical benefit in KRAS-mutant colorectal cancer. To identify mechanisms of resistance to MEKi, we employed a pharmacogenomic analysis of MEKi-sensitive versus MEKi-resistant colorectal cancer cell lines. Strikingly, interferon- and inflammatory-related gene sets were enriched in cell lines exhibiting intrinsic and acquired resistance to MEK inhibition. The bromodomain inhibitor JQ1 suppressed interferon-stimulated gene (ISG) expression and in combination with MEK inhibitors displayed synergistic effects and induced apoptosis in MEKi-resistant colorectal cancer cell lines. ISG expression was confirmed in patient-derived organoid models, which displayed resistance to trametinib and were resensitized by JQ1 co-treatment. In in vivo models of colorectal cancer, combination treatment significantly suppressed tumor growth. Our findings provide a novel explanation for the limited response to MEK inhibitors in KRAS-mutant colorectal cancer, known for its inflammatory nature. Moreover, the high expression of ISGs was associated with significantly reduced survival of colorectal cancer patients. Excitingly, we have identified novel therapeutic opportunities to overcome intrinsic and acquired resistance to MEK inhibition in colorectal cancer.

Published
2018

9. Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma

Author

Poon, Evon, primary, Liang, Tong, additional, Jamin, Yann, additional, Walz, Susanne, additional, Kwok, Colin, additional, Hakkert, Anne, additional, Barker, Karen, additional, Urban, Zuzanna, additional, Thway, Khin, additional, Zeid, Rhamy, additional, Hallsworth, Albert, additional, Box, Gary, additional, Ebus, Marli E., additional, Licciardello, Marco P., additional, Sbirkov, Yordan, additional, Lazaro, Glori, additional, Calton, Elizabeth, additional, Costa, Barbara M., additional, Valenti, Melanie, additional, De Haven Brandon, Alexis, additional, Webber, Hannah, additional, Tardif, Nicolas, additional, Almeida, Gilberto S., additional, Christova, Rossitza, additional, Boysen, Gunther, additional, Richards, Mark W., additional, Barone, Giuseppe, additional, Ford, Anthony, additional, Bayliss, Richard, additional, Clarke, Paul A., additional, De Bono, Johann, additional, Gray, Nathanael S., additional, Blagg, Julian, additional, Robinson, Simon P., additional, Eccles, Suzanne A., additional, Zheleva, Daniella, additional, Bradner, James E., additional, Molenaar, Jan, additional, Vivanco, Igor, additional, Eilers, Martin, additional, Workman, Paul, additional, Lin, Charles Y., additional, and Chesler, Louis, additional

Published
2020
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10. Characterisation of CCT271850, a selective, oral and potent MPS1 inhibitor, used to directly measure in vivo MPS1 inhibition vs therapeutic efficacy

Author

Faisal, Amir, Mak, Grace W Y, Gurden, Mark D, Xavier, Cristina P R, Anderhub, Simon J, Innocenti, Paolo, Westwood, Isaac M, Naud, Sébastien, Hayes, Angela, Box, Gary, Valenti, Melanie R, De Haven Brandon, Alexis K, O'Fee, Lisa, Schmitt, Jessica, Woodward, Hannah L, Burke, Rosemary, vanMontfort, Rob L M, Blagg, Julian, Raynaud, Florence I, Eccles, Suzanne A, Hoelder, Swen, and Linardopoulos, Spiros

Subjects
Cell Cycle Proteins, Protein Serine-Threonine Kinases, Protein-Tyrosine Kinases, HCT116 Cells, Heterocyclic Compounds, 4 or More Rings, Xenograft Model Antitumor Assays, inhibition, spindle assembly checkpoint, Mice, Cell Line, Tumor, Neoplasms, pharmacodynamics, Animals, Humans, M Phase Cell Cycle Checkpoints, Translational Therapeutics, MPS1, Protein Kinase Inhibitors
Abstract

Background: The main role of the cell cycle is to enable error-free DNA replication, chromosome segregation and cytokinesis. One of the best characterised checkpoint pathways is the spindle assembly checkpoint, which prevents anaphase onset until the appropriate attachment and tension across kinetochores is achieved. MPS1 kinase activity is essential for the activation of the spindle assembly checkpoint and has been shown to be deregulated in human tumours with chromosomal instability and aneuploidy. Therefore, MPS1 inhibition represents an attractive strategy to target cancers. Methods: To evaluate CCT271850 cellular potency, two specific antibodies that recognise the activation sites of MPS1 were used and its antiproliferative activity was determined in 91 human cancer cell lines. DLD1 cells with induced GFP-MPS1 and HCT116 cells were used in in vivo studies to directly measure MPS1 inhibition and efficacy of CCT271850 treatment. Results: CCT271850 selectively and potently inhibits MPS1 kinase activity in biochemical and cellular assays and in in vivo models. Mechanistically, tumour cells treated with CCT271850 acquire aberrant numbers of chromosomes and the majority of cells divide their chromosomes without proper alignment because of abrogation of the mitotic checkpoint, leading to cell death. We demonstrated a moderate level of efficacy of CCT271850 as a single agent in a human colorectal carcinoma xenograft model. Conclusions: CCT271850 is a potent, selective and orally bioavailable MPS1 kinase inhibitor. On the basis of in vivo pharmacodynamic vs efficacy relationships, we predict that more than 80% inhibition of MPS1 activity for at least 24 h is required to achieve tumour stasis or regression by CCT271850.

Published
2017

11. FGF7--FGFR2 autocrine signaling increases growth and chemoresistance of fusion-positive rhabdomyosarcomas.

Author

Milton, Christopher I., Selfe, Joanna, Aladowicz, Ewa, Man, Stella Y. K., Bernauer, Carolina, Missiaglia, Edoardo, Walters, Zoë S., Gatz, Susanne A., Kelsey, Anna, Generali, Melanie, Box, Gary, Valenti, Melanie, de Haven-Brandon, Alexis, Galiwango, David, Hayes, Angela, Clarke, Matthew, Izquierdo, Elisa, Gonzalez De Castro, David, Raynaud, Florence I., and Kirkin, Vladimir

Abstract

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; here, we sought to investigate the involvement and potential for therapeutic targeting of other FGFRs in this disease. Cell-based screening of FGFR inhibitors with potential for clinical repurposing (NVP-BGJ398, nintedanib, dovitinib, and ponatinib) revealed greater sensitivity of fusion-gene-positive versus fusion-gene-negative rhabdomyosarcoma cell lines and was shown to be correlated with high expression of FGFR2 and its specific ligand, FGF7. Furthermore, patient samples exhibit higher mRNA levels of FGFR2 and FGF7 in fusion-gene-positive versus fusion-gene-negative rhabdomyosarcomas. Sustained intracellular mitogen-activated protein kinase (MAPK) activity and FGF7 secretion into culture media during serum starvation of PAX3--FOXO1 rhabdomyosarcoma cells together with decreased cell viability after genetic silencing of FGFR2 or FGF7 was in keeping with a novel FGF7--FGFR2 autocrine loop. FGFR inhibition with NVP-BGJ398 reduced viability and was synergistic with SN38, the active metabolite of irinotecan. In vivo, NVP-BGJ398 abrogated xenograft growth and warrants further investigation in combination with irinotecan as a therapeutic strategy for fusion-genepositive rhabdomyosarcomas. [ABSTRACT FROM AUTHOR]

Published
2022
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12. Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma

Author

Poon, Evon, Liang, Tong, Jamin, Yann, Walz, Susanne, Kwok, Colin, Hakkert, Anne, Barker, Karen, Urban, Zuzanna, Thway, Khin, Zeid, Rhamy, Hallsworth, Albert, Box, Gary, Ebus, Marli E, Licciardello, Marco P, Sbirkov, Yordan, Lazaro, Glori, Calton, Elizabeth, Costa, Barbara M, Valenti, Melanie, De Haven Brandon, Alexis, Webber, Hannah, Tardif, Nicolas, Almeida, Gilberto S, Christova, Rossitza, Boysen, Gunther, Richards, Mark W, Barone, Giuseppe, Ford, Anthony, Bayliss, Richard, Clarke, Paul A, De Bono, Johann, Gray, Nathanael S, Blagg, Julian, Robinson, Simon P, Eccles, Suzanne A, Zheleva, Daniella, Bradner, James E, Molenaar, Jan, Vivanco, Igor, Eilers, Martin, Workman, Paul, Lin, Charles Y, Chesler, Louis, Poon, Evon, Liang, Tong, Jamin, Yann, Walz, Susanne, Kwok, Colin, Hakkert, Anne, Barker, Karen, Urban, Zuzanna, Thway, Khin, Zeid, Rhamy, Hallsworth, Albert, Box, Gary, Ebus, Marli E, Licciardello, Marco P, Sbirkov, Yordan, Lazaro, Glori, Calton, Elizabeth, Costa, Barbara M, Valenti, Melanie, De Haven Brandon, Alexis, Webber, Hannah, Tardif, Nicolas, Almeida, Gilberto S, Christova, Rossitza, Boysen, Gunther, Richards, Mark W, Barone, Giuseppe, Ford, Anthony, Bayliss, Richard, Clarke, Paul A, De Bono, Johann, Gray, Nathanael S, Blagg, Julian, Robinson, Simon P, Eccles, Suzanne A, Zheleva, Daniella, Bradner, James E, Molenaar, Jan, Vivanco, Igor, Eilers, Martin, Workman, Paul, Lin, Charles Y, and Chesler, Louis

Abstract

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 that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 - a component of the transcription elongation complex P-TEFb - bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCN-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYC065. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYC065. CYC065, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCN-amplified neuroblastoma.

Published
2020

13. Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma

Author

UU BETA RESEARCH, Poon, Evon, Liang, Tong, Jamin, Yann, Walz, Susanne, Kwok, Colin, Hakkert, Anne, Barker, Karen, Urban, Zuzanna, Thway, Khin, Zeid, Rhamy, Hallsworth, Albert, Box, Gary, Ebus, Marli E, Licciardello, Marco P, Sbirkov, Yordan, Lazaro, Glori, Calton, Elizabeth, Costa, Barbara M, Valenti, Melanie, De Haven Brandon, Alexis, Webber, Hannah, Tardif, Nicolas, Almeida, Gilberto S, Christova, Rossitza, Boysen, Gunther, Richards, Mark W, Barone, Giuseppe, Ford, Anthony, Bayliss, Richard, Clarke, Paul A, De Bono, Johann, Gray, Nathanael S, Blagg, Julian, Robinson, Simon P, Eccles, Suzanne A, Zheleva, Daniella, Bradner, James E, Molenaar, Jan, Vivanco, Igor, Eilers, Martin, Workman, Paul, Lin, Charles Y, Chesler, Louis, UU BETA RESEARCH, Poon, Evon, Liang, Tong, Jamin, Yann, Walz, Susanne, Kwok, Colin, Hakkert, Anne, Barker, Karen, Urban, Zuzanna, Thway, Khin, Zeid, Rhamy, Hallsworth, Albert, Box, Gary, Ebus, Marli E, Licciardello, Marco P, Sbirkov, Yordan, Lazaro, Glori, Calton, Elizabeth, Costa, Barbara M, Valenti, Melanie, De Haven Brandon, Alexis, Webber, Hannah, Tardif, Nicolas, Almeida, Gilberto S, Christova, Rossitza, Boysen, Gunther, Richards, Mark W, Barone, Giuseppe, Ford, Anthony, Bayliss, Richard, Clarke, Paul A, De Bono, Johann, Gray, Nathanael S, Blagg, Julian, Robinson, Simon P, Eccles, Suzanne A, Zheleva, Daniella, Bradner, James E, Molenaar, Jan, Vivanco, Igor, Eilers, Martin, Workman, Paul, Lin, Charles Y, and Chesler, Louis

Published
2020

14. Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19

Author

Mallinger, Aurélie, Schiemann, Kai, Rink, Christian, Stieber, Frank, Calderini, Michel, Crumpler, Simon, Stubbs, Mark, Adeniji-Popoola, Olajumoke, Poeschke, Oliver, Busch, Michael, Czodrowski, Paul, Musil, Djordje, Schwarz, Daniel, Ortiz-Ruiz, Maria-Jesus, Schneider, Richard, Thai, Ching, Valenti, Melanie, de Haven Brandon, Alexis, Burke, Rosemary, Workman, Paul, Dale, Trevor, Wienke, Dirk, Clarke, Paul A., Esdar, Christina, Raynaud, Florence I., Eccles, Suzanne A., Rohdich, Felix, and Blagg, Julian

Subjects
Male, Models, Molecular, Dose-Response Relationship, Drug, Molecular Structure, Administration, Oral, Aminopyridines, Biological Availability, Neoplasms, Experimental, Cyclin-Dependent Kinase 8, Xenograft Model Antitumor Assays, Article, Cyclin-Dependent Kinases, Rats, Small Molecule Libraries, Mice, Structure-Activity Relationship, Dogs, Solubility, Drug Discovery, Animals, Humans, Female, Caco-2 Cells, Rats, Wistar
Abstract

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 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of cancer.

Published
2016

15. The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eμ-MYC driven B-cell lymphoma

Author

Walton, Mike I., Eve, Paul D., Hayes, Angela, Henley, Alan T., Valenti, Melanie R., De Haven Brandon, Alexis K., Box, Gary, Boxall, Kathy J., Tall, Matthew, Swales, Karen, Matthews, Thomas P., McHardy, Tatiana, Lainchbury, Michael, Osborne, James, Hunter, Jill E., Perkins, Neil D., Aherne, G. Wynne, Reader, John C., Raynaud, Florence I., Eccles, Suzanne A., Collins, Ian, and Garrett, Michelle D.

Subjects
Lung Neoplasms, Lymphoma, B-Cell, CHK1, Mice, Nude, Apoptosis, Mice, Transgenic, Irinotecan, environment and public health, CCT245737, Deoxycytidine, Proto-Oncogene Proteins c-myc, Proto-Oncogene Proteins p21(ras), Mice, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Antineoplastic Combined Chemotherapy Protocols, CDC2 Protein Kinase, Animals, Humans, antitumor activity, 4-Aminopyridine, Mice, Inbred BALB C, biomarker assay, Drug Synergism, Cell Cycle Checkpoints, Xenograft Model Antitumor Assays, Gemcitabine, Cyclin-Dependent Kinases, enzymes and coenzymes (carbohydrates), Checkpoint Kinase 2, Pyrazines, Checkpoint Kinase 1, Camptothecin, biological phenomena, cell phenomena, and immunity, pharmacology, HT29 Cells, Research Paper, DNA Damage
Abstract

CCT245737 is the first orally active, clinical development candidate CHK1 inhibitor to be described. The IC50 was 1.4 nM against CHK1 enzyme and it exhibited1,000-fold selectivity against CHK2 and CDK1. CCT245737 potently inhibited cellular CHK1 activity (IC50 30-220 nM) and enhanced gemcitabine and SN38 cytotoxicity in multiple human tumor cell lines and human tumor xenograft models. Mouse oral bioavailability was complete (100%) with extensive tumor exposure. Genotoxic-induced CHK1 activity (pS296 CHK1) and cell cycle arrest (pY15 CDK1) were inhibited both in vitro and in human tumor xenografts by CCT245737, causing increased DNA damage and apoptosis. Uniquely, we show CCT245737 enhanced gemcitabine antitumor activity to a greater degree than for higher doses of either agent alone, without increasing toxicity, indicating a true therapeutic advantage for this combination. Furthermore, development of a novel ELISA assay for pS296 CHK1 autophosphorylation, allowed the quantitative measurement of target inhibition in a RAS mutant human tumor xenograft of NSCLC at efficacious doses of CCT245737. Finally, CCT245737 also showed significant single-agent activity against a MYC-driven mouse model of B-cell lymphoma. In conclusion, CCT245737 is a new CHK1 inhibitor clinical development candidate scheduled for a first in man Phase I clinical trial, that will use the novel pS296 CHK1 ELISA to monitor target inhibition.

Published
2015

16. Discovery of Potent, Orally Bioavailable, Small-Molecule Inhibitors of WNT Signaling from a Cell-Based Pathway Screen

Author

Mallinger, Aurélie, Crumpler, Simon, Pichowicz, Mark, Waalboer, Dennis, Stubbs, Mark, Adeniji-Popoola, Olajumoke, Wood, Bozena, Smith, Elizabeth, Thai, Ching, Henley, Alan T., Georgi, Katrin, Court, William, Hobbs, Steve, Box, Gary, Ortiz-Ruiz, Maria-Jesus, Valenti, Melanie, De Haven Brandon, Alexis, TePoele, Robert, Leuthner, Birgitta, Workman, Paul, Aherne, Wynne, Poeschke, Oliver, Dale, Trevor, Wienke, Dirk, Esdar, Christina, Rohdich, Felix, Raynaud, Florence, Clarke, Paul A., Eccles, Suzanne A., Stieber, Frank, Schiemann, Kai, and Blagg, Julian

Subjects
Models, Molecular, Dose-Response Relationship, Drug, Molecular Structure, Pyridines, Drug Evaluation, Preclinical, Administration, Oral, Biological Availability, Antineoplastic Agents, Crystallography, X-Ray, Xenograft Model Antitumor Assays, Article, Small Molecule Libraries, Disease Models, Animal, Mice, Structure-Activity Relationship, Cell Line, Tumor, Animals, Humans, Biological Assay, Spiro Compounds, Colorectal Neoplasms, Luciferases, Wnt Signaling Pathway, Cell Proliferation
Abstract

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 pyridine 9 using a high-throughput cell-based reporter assay of WNT pathway activity. We demonstrate a twisted conformation about the pyridine-piperidine bond of 9 by small-molecule X-ray crystallography. Medicinal chemistry optimization to maintain this twisted conformation, cognisant of physicochemical properties likely to maintain good cell permeability, led to 74 (CCT251545), a potent small-molecule inhibitor of WNT signaling with good oral pharmacokinetics. We demonstrate inhibition of WNT pathway activity in a solid human tumor xenograft model with evidence for tumor growth inhibition following oral dosing. This work provides a successful example of hypothesis-driven medicinal chemistry optimization from a singleton hit against a cell-based pathway assay without knowledge of the biochemical target.

Published
2015

17. Modulation of Plasma Metabolite Biomarkers of the MAPK Pathway with MEK Inhibitor RO4987655: Pharmacodynamic and Predictive Potential in Metastatic Melanoma

Author

Ang, Joo Ern, primary, Pal, Akos, additional, Asad, Yasmin J., additional, Henley, Alan T., additional, Valenti, Melanie, additional, Box, Gary, additional, de haven Brandon, Alexis, additional, Revell, Victoria L., additional, Skene, Debra J., additional, Venturi, Miro, additional, Rueger, Ruediger, additional, Meresse, Valerie, additional, Eccles, Suzanne A., additional, de Bono, Johann S., additional, Kaye, Stanley B., additional, Workman, Paul, additional, Banerji, Udai, additional, and Raynaud, Florence I., additional

Published
2017
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18. Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases

Author

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

Published
2016
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19. Abstract 4355: Elucidation of the different roles of CDK8 and CDK19 in colorectal cancer (CRC) using CRISPR gene editing technology

Author

Ortiz Ruiz, Maria J., primary, Popoola, Olajumoke, additional, Mallinger, Aurelie, additional, Gowan, Sharon, additional, Court, Will, additional, Box, Gary, additional, Valenti, Melanie, additional, De Haven Brandon, Alexis, additional, Te-Poele, Robert, additional, Workman, Paul, additional, Schiemann, Kai, additional, Esdar, Cristina, additional, Wienke, Dirk, additional, Blagg, Julian, additional, Clarke, Paul, additional, and Eccles, Suzanne A., additional

Published
2016
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20. Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation

Author

Ang, Joo Ern, primary, Pandher, Rupinder, additional, Ang, Joo Chew, additional, Asad, Yasmin J., additional, Henley, Alan T., additional, Valenti, Melanie, additional, Box, Gary, additional, de Haven Brandon, Alexis, additional, Baird, Richard D., additional, Friedman, Lori, additional, Derynck, Mika, additional, Vanhaesebroeck, Bart, additional, Eccles, Suzanne A., additional, Kaye, Stan B., additional, Workman, Paul, additional, de Bono, Johann S., additional, and Raynaud, Florence I., additional

Published
2016
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21. Dual Blockade of the PI3K/AKT/mTOR (AZD8055) and RAS/MEK/ERK (AZD6244) Pathways Synergistically Inhibits Rhabdomyosarcoma Cell Growth In Vitro and In Vivo

Author

Renshaw, Jane, primary, Taylor, Kathryn R., additional, Bishop, Ryan, additional, Valenti, Melanie, additional, De Haven Brandon, Alexis, additional, Gowan, Sharon, additional, Eccles, Suzanne A., additional, Ruddle, Ruth R., additional, Johnson, Louise D., additional, Raynaud, Florence I., additional, Selfe, Joanna L., additional, Thway, Khin, additional, Pietsch, Torsten, additional, Pearson, Andrew D., additional, and Shipley, Janet, additional

Published
2013
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23. Abstract 3517: Changes in plasma components of β-oxidation as a pharmacodynamic (PD) biomarker of PI3K inhibition by GDC-0941, a potent, pan-inhibitor of Class I phosphatidyl-inositol-3-kinase (PI3K).

Author

Ang, Joo Ern, primary, Pandher, Rupinder, additional, Asad, Yasmin, additional, Henley, Alan, additional, Valenti, Melanie, additional, Box, Gary, additional, de haven Brandon, Alexis, additional, Eccles, Suzan, additional, Workman, Paul, additional, de Bono, Johann S., additional, and Raynaud, Florence I., additional

Published
2013
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24. CCT244747 Is a Novel Potent and Selective CHK1 Inhibitor with Oral Efficacy Alone and in Combination with Genotoxic Anticancer Drugs

Author

Walton, Mike I., primary, Eve, Paul D., additional, Hayes, Angela, additional, Valenti, Melanie R., additional, De Haven Brandon, Alexis K., additional, Box, Gary, additional, Hallsworth, Albert, additional, Smith, Elizabeth L., additional, Boxall, Kathy J., additional, Lainchbury, Michael, additional, Matthews, Thomas P., additional, Jamin, Yann, additional, Robinson, Simon P., additional, Aherne, G. Wynne, additional, Reader, John C., additional, Chesler, Louis, additional, Raynaud, Florence I., additional, Eccles, Suzanne A., additional, Collins, Ian, additional, and Garrett, Michelle D., additional

Published
2012
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25. AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity

Author

Yap, Timothy A., primary, Walton, Mike I., additional, Grimshaw, Kyla M., additional, te Poele, Robert H., additional, Eve, Paul D., additional, Valenti, Melanie R., additional, de Haven Brandon, Alexis K., additional, Martins, Vanessa, additional, Zetterlund, Anna, additional, Heaton, Simon P., additional, Heinzmann, Kathrin, additional, Jones, Paul S., additional, Feltell, Ruth E., additional, Reule, Matthias, additional, Woodhead, Steven J., additional, Davies, Thomas G., additional, Lyons, John F., additional, Raynaud, Florence I., additional, Eccles, Suzanne A., additional, Workman, Paul, additional, Thompson, Neil T., additional, and Garrett, Michelle D., additional

Published
2012
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26. Abstract 928: The novel clinical candidate AT13148 is an oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity and demonstrates a mechanism of action distinct from AKT inhibitors

Author

Yap, Timothy A., primary, Walton, Michael I., additional, Grimshaw, Kyla M., additional, Poele, Robert H. te, additional, Eve, Paul D., additional, Valenti, Melanie R., additional, de Haven Brandon, Alexis K., additional, Martins, Vanessa, additional, Zetterlund, Anna, additional, Heaton, Simon P., additional, Heinzmann, Kathrin, additional, Jones, Paul S., additional, Feltell, Ruth E., additional, Reule, Matthias, additional, Woodhead, Steven J., additional, Davies, Thomas G., additional, Lyons, John F., additional, Raynaud, Florence I., additional, Eccles, Suzanne A., additional, Workman, Paul, additional, Thompson, Neil T., additional, and Garrett, Michelle D., additional

Published
2012
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27. Resistance to Selective FLT3 Inhibitors, Driven by FLT3 Ligand and FLT3 Point Mutations, Can Be Overcome with the Dual FLT3-Aurora Kinase Inhibitor CCT241736,

Author

Moore, Andrew S., primary, Faisal, Amir, additional, Bavetsias, Vassilios, additional, de Castro, David Gonzalez, additional, Sun, Chongbo, additional, Atrash, Butrus, additional, Valenti, Melanie, additional, de Haven Brandon, Alexis, additional, Avery, Sian, additional, Pearson, Andrew DJ, additional, Workman, Paul, additional, Blagg, Julian, additional, Raynaud, Florence I, additional, Eccles, Suzanne A, additional, and Linardopoulos, Spiros, additional

Published
2011
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28. Abstract A235: Structure-guided evolution of potent and selective oral inhibitors of CHK1 through scaffold morphing.

Author

Matthews, Thomas P., primary, Klair, Suki, additional, Cheung, Kwai-Ming J., additional, Scanlon, Jane, additional, Lainchbury, Michael, additional, Piton, Nelly, additional, Fisher, Martin, additional, Cherry, Michael, additional, Boxall, Kathy, additional, Walton, Michael I., additional, Westwood, Isaac M., additional, Hayes, Angela, additional, Eve, Paul, additional, Valenti, Melanie, additional, de Haven Brandon, Alexis, additional, Box, Gary, additional, van Montfort, Rob L. M., additional, Williams, David H., additional, Aherne, Wynne, additional, Raynaud, Florence I., additional, Eccles, Suzanne A., additional, Garrett, Michelle D., additional, Reader, John C., additional, and Collins, Ian, additional

Published
2011
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29. Abstract A228: CCT244747 is a novel, potent and selective inhibitor of CHK1 with oral efficacy both alone in neuroblastoma and in combination with genotoxic chemotherapeutic agents.

Author

Walton, Michael I., primary, Eve, Paul E., additional, Hayes, Angela, additional, Valenti, Melanie R., additional, de Haven Brandon, Alexis K., additional, Box, Gary, additional, Hallsworth, Albert, additional, Smith, Elizabeth L., additional, Boxall, Kathy J., additional, Lainchbury, Michael, additional, Matthews, Thomas P., additional, Jamin, Yann, additional, Robinson, Simon P., additional, Aherne, G. Wynne, additional, Reader, John C., additional, Chesler, Louis, additional, Raynaud, Florence I., additional, Eccles, Suzanne E., additional, Collins, Ian, additional, and Garrett, Michelle D., additional

Published
2011
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30. Enhanced Efficacy of IGF1R Inhibition in Pediatric Glioblastoma by Combinatorial Targeting of PDGFRα/β

Author

Bielen, Aleksandra, primary, Perryman, Lara, additional, Box, Gary M., additional, Valenti, Melanie, additional, de Haven Brandon, Alexis, additional, Martins, Vanessa, additional, Jury, Alexa, additional, Popov, Sergey, additional, Gowan, Sharon, additional, Jeay, Sebastien, additional, Raynaud, Florence I., additional, Hofmann, Francesco, additional, Hargrave, Darren, additional, Eccles, Suzanne A., additional, and Jones, Chris, additional

Published
2011
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31. Abstract 3554: CCT137690, a dual inhibitor of Aurora and FLT3 kinases, sensitizes FLT3-ITD positive acute myeloid leukemia and overcomes resistance to selective FLT3-inhibition

Author

Moore, Andrew S., primary, Faisal, Amir, additional, Bavetsias, Vassilios, additional, Sun, Chongbo, additional, Atrash, Butrus, additional, Valenti, Melanie, additional, de Haven Brandon, Alexis, additional, Avery, Sian, additional, de Castro, David Gonzalez, additional, Raynaud, Florence I., additional, Workman, Paul, additional, Pearson, Andrew DJ, additional, Blagg, Julian, additional, Eccles, Suzanne A., additional, and Linardopoulos, Spiros, additional

Published
2011
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32. Preclinical Pharmacology, Antitumor Activity, and Development of Pharmacodynamic Markers for the Novel, Potent AKT Inhibitor CCT128930

Author

Yap, Timothy A., primary, Walton, Mike I., additional, Hunter, Lisa-Jane K., additional, Valenti, Melanie, additional, de Haven Brandon, Alexis, additional, Eve, Paul D., additional, Ruddle, Ruth, additional, Heaton, Simon P., additional, Henley, Alan, additional, Pickard, Lisa, additional, Vijayaraghavan, Gowri, additional, Caldwell, John J., additional, Thompson, Neil T., additional, Aherne, Wynne, additional, Raynaud, Florence I., additional, Eccles, Suzanne A., additional, Workman, Paul, additional, Collins, Ian, additional, and Garrett, Michelle D., additional

Published
2011
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33. Dual Inhibition of Aurora and FLT3 Kinases by CCT137690: A Novel Treatment Strategy Against FLT3-ITD Positive AML In Vitro and In Vivo

Author

Moore, Andrew S, primary, Faisal, Amir, additional, Bavetsias, Vassilios, additional, Sun, Chongbo, additional, Atrash, Butrus, additional, Valenti, Melanie, additional, de Haven Brandon, Alexis, additional, Avery, Sian, additional, Raynaud, Florence I, additional, Workman, Paul, additional, Pearson, Andrew DJ, additional, Blagg, Julian, additional, Eccles, Suzanne A, additional, and Linardopoulos, Spiros, additional

Published
2010
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34. The Preclinical Pharmacology and Therapeutic Activity of the Novel CHK1 Inhibitor SAR-020106

Author

Walton, Michael I., primary, Eve, Paul D., additional, Hayes, Angela, additional, Valenti, Melanie, additional, De Haven Brandon, Alexis, additional, Box, Gary, additional, Boxall, Kathy J., additional, Aherne, G. Wynne, additional, Eccles, Suzanne A., additional, Raynaud, Florence I., additional, Williams, David H., additional, Reader, John C., additional, Collins, Ian, additional, and Garrett, Michelle D., additional

Published
2010
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35. Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941

Author

Raynaud, Florence I., primary, Eccles, Suzanne A., additional, Patel, Sonal, additional, Alix, Sonia, additional, Box, Gary, additional, Chuckowree, Irina, additional, Folkes, Adrian, additional, Gowan, Sharon, additional, De Haven Brandon, Alexis, additional, Di Stefano, Francesca, additional, Hayes, Angela, additional, Henley, Alan T., additional, Lensun, Letitia, additional, Pergl-Wilson, Giles, additional, Robson, Anthony, additional, Saghir, Nahid, additional, Zhyvoloup, Alexander, additional, McDonald, Edward, additional, Sheldrake, Peter, additional, Shuttleworth, Stephen, additional, Valenti, Melanie, additional, Wan, Nan Chi, additional, Clarke, Paul A., additional, and Workman, Paul, additional

Published
2009
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36. Small-Molecule Activation of p53 Blocks Hypoxia-Inducible Factor 1α and Vascular Endothelial Growth Factor Expression In Vivo and Leads to Tumor Cell Apoptosis in Normoxia and Hypoxia

Author

Yang, Jun, primary, Ahmed, Afshan, additional, Poon, Evon, additional, Perusinghe, Nina, additional, de Haven Brandon, Alexis, additional, Box, Gary, additional, Valenti, Melanie, additional, Eccles, Suzanne, additional, Rouschop, Kasper, additional, Wouters, Brad, additional, and Ashcroft, Margaret, additional

Published
2009
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37. NVP-AUY922: A Novel Heat Shock Protein 90 Inhibitor Active against Xenograft Tumor Growth, Angiogenesis, and Metastasis

Author

Eccles, Suzanne A., primary, Massey, Andy, additional, Raynaud, Florence I., additional, Sharp, Swee Y., additional, Box, Gary, additional, Valenti, Melanie, additional, Patterson, Lisa, additional, de Haven Brandon, Alexis, additional, Gowan, Sharon, additional, Boxall, Frances, additional, Aherne, Wynne, additional, Rowlands, Martin, additional, Hayes, Angela, additional, Martins, Vanessa, additional, Urban, Frederique, additional, Boxall, Kathy, additional, Prodromou, Chrisostomos, additional, Pearl, Laurence, additional, James, Karen, additional, Matthews, Thomas P., additional, Cheung, Kwai-Ming, additional, Kalusa, Andrew, additional, Jones, Keith, additional, McDonald, Edward, additional, Barril, Xavier, additional, Brough, Paul A., additional, Cansfield, Julie E., additional, Dymock, Brian, additional, Drysdale, Martin J., additional, Finch, Harry, additional, Howes, Rob, additional, Hubbard, Roderick E., additional, Surgenor, Alan, additional, Webb, Paul, additional, Wood, Mike, additional, Wright, Lisa, additional, and Workman, Paul, additional

Published
2008
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39. Pharmacologic Characterization of a Potent Inhibitor of Class I Phosphatidylinositide 3-Kinases

Author

Raynaud, Florence I., primary, Eccles, Suzanne, additional, Clarke, Paul A., additional, Hayes, Angela, additional, Nutley, Bernard, additional, Alix, Sonia, additional, Henley, Alan, additional, Di-Stefano, Francesca, additional, Ahmad, Zahida, additional, Guillard, Sandrine, additional, Bjerke, Lynn M., additional, Kelland, Lloyd, additional, Valenti, Melanie, additional, Patterson, Lisa, additional, Gowan, Sharon, additional, de Haven Brandon, Alexis, additional, Hayakawa, Masahiko, additional, Kaizawa, Hiroyuki, additional, Koizumi, Tomonubu, additional, Ohishi, Takahide, additional, Patel, Sonal, additional, Saghir, Nahid, additional, Parker, Peter, additional, Waterfield, Mike, additional, and Workman, Paul, additional

Published
2007
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41. The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eµ-MYC driven B-cell lymphoma.

Author

Walton MI, Eve PD, Hayes A, Henley AT, Valenti MR, De Haven Brandon AK, Box G, Boxall KJ, Tall M, Swales K, Matthews TP, McHardy T, Lainchbury M, Osborne J, Hunter JE, Perkins ND, Aherne GW, Reader JC, Raynaud FI, Eccles SA, Collins I, and Garrett MD

Subjects
4-Aminopyridine pharmacokinetics, 4-Aminopyridine pharmacology, Animals, Antineoplastic Combined Chemotherapy Protocols pharmacology, Apoptosis drug effects, CDC2 Protein Kinase, Camptothecin analogs & derivatives, Camptothecin pharmacology, Cell Cycle Checkpoints drug effects, Cell Line, Tumor, Checkpoint Kinase 1 metabolism, Checkpoint Kinase 2 antagonists & inhibitors, Cyclin-Dependent Kinases antagonists & inhibitors, DNA Damage drug effects, Deoxycytidine analogs & derivatives, Deoxycytidine pharmacology, Drug Synergism, HT29 Cells, Humans, Irinotecan, Mice, Mice, Inbred BALB C, Mice, Nude, Mice, Transgenic, Pyrazines pharmacokinetics, Gemcitabine, 4-Aminopyridine analogs & derivatives, Carcinoma, Non-Small-Cell Lung drug therapy, Checkpoint Kinase 1 drug effects, Lung Neoplasms drug therapy, Lymphoma, B-Cell drug therapy, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins p21(ras) genetics, Pyrazines pharmacology, Xenograft Model Antitumor Assays
Abstract

CCT245737 is the first orally active, clinical development candidate CHK1 inhibitor to be described. The IC50 was 1.4 nM against CHK1 enzyme and it exhibited>1,000-fold selectivity against CHK2 and CDK1. CCT245737 potently inhibited cellular CHK1 activity (IC50 30-220 nM) and enhanced gemcitabine and SN38 cytotoxicity in multiple human tumor cell lines and human tumor xenograft models. Mouse oral bioavailability was complete (100%) with extensive tumor exposure. Genotoxic-induced CHK1 activity (pS296 CHK1) and cell cycle arrest (pY15 CDK1) were inhibited both in vitro and in human tumor xenografts by CCT245737, causing increased DNA damage and apoptosis. Uniquely, we show CCT245737 enhanced gemcitabine antitumor activity to a greater degree than for higher doses of either agent alone, without increasing toxicity, indicating a true therapeutic advantage for this combination. Furthermore, development of a novel ELISA assay for pS296 CHK1 autophosphorylation, allowed the quantitative measurement of target inhibition in a RAS mutant human tumor xenograft of NSCLC at efficacious doses of CCT245737. Finally, CCT245737 also showed significant single-agent activity against a MYC-driven mouse model of B-cell lymphoma. In conclusion, CCT245737 is a new CHK1 inhibitor clinical development candidate scheduled for a first in man Phase I clinical trial, that will use the novel pS296 CHK1 ELISA to monitor target inhibition.

Published
2016
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