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1. Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones

Author

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

Published
2023
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2. Supplementary Table 5A from AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity

Author

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

Published
2023
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3. Supplementary Figure 5 from 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., primary, Hayes, Angela, primary, Valenti, Melanie R., primary, De Haven Brandon, Alexis K., primary, Box, Gary, primary, Hallsworth, Albert, primary, Smith, Elizabeth L., primary, Boxall, Kathy J., primary, Lainchbury, Michael, primary, Matthews, Thomas P., primary, Jamin, Yann, primary, Robinson, Simon P., primary, Aherne, G. Wynne, primary, Reader, John C., primary, Chesler, Louis, primary, Raynaud, Florence I., primary, Eccles, Suzanne A., primary, Collins, Ian, primary, and Garrett, Michelle D., primary

Published
2023
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4. Supplementary Table 6A from AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity

Author

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

Published
2023
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5. Supplementary Figure 3 from 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., primary, Hayes, Angela, primary, Valenti, Melanie R., primary, De Haven Brandon, Alexis K., primary, Box, Gary, primary, Hallsworth, Albert, primary, Smith, Elizabeth L., primary, Boxall, Kathy J., primary, Lainchbury, Michael, primary, Matthews, Thomas P., primary, Jamin, Yann, primary, Robinson, Simon P., primary, Aherne, G. Wynne, primary, Reader, John C., primary, Chesler, Louis, primary, Raynaud, Florence I., primary, Eccles, Suzanne A., primary, Collins, Ian, primary, and Garrett, Michelle D., primary

Published
2023
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6. Supplementary Figure 4 from 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., primary, Hayes, Angela, primary, Valenti, Melanie R., primary, De Haven Brandon, Alexis K., primary, Box, Gary, primary, Hallsworth, Albert, primary, Smith, Elizabeth L., primary, Boxall, Kathy J., primary, Lainchbury, Michael, primary, Matthews, Thomas P., primary, Jamin, Yann, primary, Robinson, Simon P., primary, Aherne, G. Wynne, primary, Reader, John C., primary, Chesler, Louis, primary, Raynaud, Florence I., primary, Eccles, Suzanne A., primary, Collins, Ian, primary, and Garrett, Michelle D., primary

Published
2023
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7. Supplementary Figure Legend from 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., primary, Hayes, Angela, primary, Valenti, Melanie R., primary, De Haven Brandon, Alexis K., primary, Box, Gary, primary, Hallsworth, Albert, primary, Smith, Elizabeth L., primary, Boxall, Kathy J., primary, Lainchbury, Michael, primary, Matthews, Thomas P., primary, Jamin, Yann, primary, Robinson, Simon P., primary, Aherne, G. Wynne, primary, Reader, John C., primary, Chesler, Louis, primary, Raynaud, Florence I., primary, Eccles, Suzanne A., primary, Collins, Ian, primary, and Garrett, Michelle D., primary

Published
2023
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8. Supplementary Figures 1-7, Tables 1-4 from AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity

Author

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

Published
2023
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9. Supplementary Table 1 from 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., primary, Hayes, Angela, primary, Valenti, Melanie R., primary, De Haven Brandon, Alexis K., primary, Box, Gary, primary, Hallsworth, Albert, primary, Smith, Elizabeth L., primary, Boxall, Kathy J., primary, Lainchbury, Michael, primary, Matthews, Thomas P., primary, Jamin, Yann, primary, Robinson, Simon P., primary, Aherne, G. Wynne, primary, Reader, John C., primary, Chesler, Louis, primary, Raynaud, Florence I., primary, Eccles, Suzanne A., primary, Collins, Ian, primary, and Garrett, Michelle D., primary

Published
2023
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10. Supplementary Table 2 from 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., primary, Hayes, Angela, primary, Valenti, Melanie R., primary, De Haven Brandon, Alexis K., primary, Box, Gary, primary, Hallsworth, Albert, primary, Smith, Elizabeth L., primary, Boxall, Kathy J., primary, Lainchbury, Michael, primary, Matthews, Thomas P., primary, Jamin, Yann, primary, Robinson, Simon P., primary, Aherne, G. Wynne, primary, Reader, John C., primary, Chesler, Louis, primary, Raynaud, Florence I., primary, Eccles, Suzanne A., primary, Collins, Ian, primary, and Garrett, Michelle D., primary

Published
2023
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11. Supplementary Tables 3 - 6 from 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., primary, Hayes, Angela, primary, Valenti, Melanie R., primary, De Haven Brandon, Alexis K., primary, Box, Gary, primary, Hallsworth, Albert, primary, Smith, Elizabeth L., primary, Boxall, Kathy J., primary, Lainchbury, Michael, primary, Matthews, Thomas P., primary, Jamin, Yann, primary, Robinson, Simon P., primary, Aherne, G. Wynne, primary, Reader, John C., primary, Chesler, Louis, primary, Raynaud, Florence I., primary, Eccles, Suzanne A., primary, Collins, Ian, primary, and Garrett, Michelle D., primary

Published
2023
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12. Supplementary Methods, Figure Legends 1-7 from AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity

Author

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

Published
2023
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13. Supplementary Figure 2 from 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., primary, Hayes, Angela, primary, Valenti, Melanie R., primary, De Haven Brandon, Alexis K., primary, Box, Gary, primary, Hallsworth, Albert, primary, Smith, Elizabeth L., primary, Boxall, Kathy J., primary, Lainchbury, Michael, primary, Matthews, Thomas P., primary, Jamin, Yann, primary, Robinson, Simon P., primary, Aherne, G. Wynne, primary, Reader, John C., primary, Chesler, Louis, primary, Raynaud, Florence I., primary, Eccles, Suzanne A., primary, Collins, Ian, primary, and Garrett, Michelle D., primary

Published
2023
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14. Supplementary Figure 1 from 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., primary, Hayes, Angela, primary, Valenti, Melanie R., primary, De Haven Brandon, Alexis K., primary, Box, Gary, primary, Hallsworth, Albert, primary, Smith, Elizabeth L., primary, Boxall, Kathy J., primary, Lainchbury, Michael, primary, Matthews, Thomas P., primary, Jamin, Yann, primary, Robinson, Simon P., primary, Aherne, G. Wynne, primary, Reader, John C., primary, Chesler, Louis, primary, Raynaud, Florence I., primary, Eccles, Suzanne A., primary, Collins, Ian, primary, and Garrett, Michelle D., primary

Published
2023
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15. Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo

Author

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

Published
2022
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16. 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

17. 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

18. Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737)

Author

Osborne, James D., primary, Matthews, Thomas P., additional, McHardy, Tatiana, additional, Proisy, Nicolas, additional, Cheung, Kwai-Ming J., additional, Lainchbury, Michael, additional, Brown, Nathan, additional, Walton, Michael I., additional, Eve, Paul D., additional, Boxall, Katherine J., additional, Hayes, Angela, additional, Henley, Alan T., additional, Valenti, Melanie R., additional, De Haven Brandon, Alexis K., additional, Box, Gary, additional, Jamin, Yann, additional, Robinson, Simon P., additional, Westwood, Isaac M., additional, van Montfort, Rob L. M., additional, Leonard, Philip M., additional, Lamers, Marieke B. A. C., additional, Reader, John C., additional, Aherne, G. Wynne, additional, Raynaud, Florence I., additional, Eccles, Suzanne A., additional, Garrett, Michelle D., additional, and Collins, Ian, additional

Published
2016
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19. Discovery of 3-Alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as Selective, Orally Bioavailable CHK1 Inhibitors

Author

Lainchbury, Michael, primary, Matthews, Thomas P., additional, McHardy, Tatiana, additional, Boxall, Kathy J., additional, Walton, Michael I., additional, Eve, Paul D., additional, Hayes, Angela, additional, Valenti, Melanie R., additional, de Haven Brandon, Alexis K., additional, Box, Gary, additional, Aherne, G. Wynne, additional, Reader, John C., additional, Raynaud, Florence I., additional, Eccles, Suzanne A., additional, Garrett, Michelle D., additional, and Collins, Ian, additional

Published
2012
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20. 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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21. 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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22. 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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23. 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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25. Application of Meso Scale Technology for the Measurement of Phosphoproteins in Human Tumor Xenografts

Author

Gowan, Sharon M., primary, Hardcastle, Anthea, additional, Hallsworth, Albert E., additional, Valenti, Melanie R., additional, Hunter, Lisa-Jane K., additional, de Haven Brandon, Alexis K., additional, Garrett, Michelle D., additional, Raynaud, Florence, additional, Workman, Paul, additional, Aherne, Wynne, additional, and Eccles, Suzanne A., additional

Published
2007
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26. Discovery of an In VivoChemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones

Author

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., and Hoelder, Swen

Abstract

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 inhibition of BCL6. We sought to improve the cellular potency and in vivoexposure of the non-degrading isomer, CCT373567, of our recently published degrader, CCT373566. The major limitation of our inhibitors was their high topological polar surface areas (TPSA), leading to increased efflux ratios. Reducing the molecular weight allowed us to remove polarity and decrease TPSA without considerably reducing solubility. Careful optimization of these properties, as guided by pharmacokinetic studies, led to the discovery of CCT374705, a potent inhibitor of BCL6 with a good in vivoprofile. Modest in vivoefficacy was achieved in a lymphoma xenograft mouse model after oral dosing.

Published
2023
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28. 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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