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26 results on '"Lamont, Gillian M."'

2. Development of a Series of Pyrrolopyridone MAT2A Inhibitors.

Author

Atkinson, Stephen J., Bagal, Sharan K., Argyrou, Argyrides, Askin, Sean, Cheung, Tony, Chiarparin, Elisabetta, Coen, Muireann, Collie, Iain T., Dale, Ian L., De Fusco, Claudia, Dillman, Keith, Evans, Laura, Feron, Lyman J., Foster, Alison J., Grondine, Michael, Kantae, Vasudev, Lamont, Gillian M., Lamont, Scott, Lynch, James T., and Nilsson Lill, Sten

Published
2024
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3. AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity

Author

Fok, Jacqueline H. L., Ramos-Montoya, Antonio, Vazquez-Chantada, Mercedes, Wijnhoven, Paul W. G., Follia, Valeria, James, Neil, Farrington, Paul M., Karmokar, Ankur, Willis, Sophie E., Cairns, Jonathan, Nikkilä, Jenni, Beattie, David, Lamont, Gillian M., Finlay, M. Raymond V., Wilson, Joanne, Smith, Aaron, O’Connor, Lenka Oplustil, Ling, Stephanie, Fawell, Stephen E., O’Connor, Mark J., Hollingsworth, Simon J., Dean, Emma, Goldberg, Frederick W., Davies, Barry R., and Cadogan, Elaine B.

Published
2019
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4. Chemical Biology Approaches Confirm MCT4 as the Therapeutic Target of a Cellular Optimized Hit

Author

Kawatkar, Aarti, primary, Clark, Roger A., additional, Hopcroft, Lorna, additional, Roaquin, Debora Ann, additional, Tomlinson, Ronald, additional, Zuhl, Andrea M., additional, Lamont, Gillian M., additional, Kettle, Jason G., additional, Critchlow, Susan E., additional, Castaldi, M. Paola, additional, Goldberg, Frederick W., additional, and Zhang, Andrew X., additional

Published
2023
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5. Discovery of Clinical Candidate AZD0095, a Selective Inhibitor of Monocarboxylate Transporter 4 (MCT4) for Oncology

Author

Goldberg, Frederick W., primary, Kettle, Jason G., additional, Lamont, Gillian M., additional, Buttar, David, additional, Ting, Attilla K. T., additional, McGuire, Thomas M., additional, Cook, Calum R., additional, Beattie, David, additional, Morentin Gutierrez, Pablo, additional, Kavanagh, Stefan L., additional, Komen, Jasper C., additional, Kawatkar, Aarti, additional, Clark, Roger, additional, Hopcroft, Lorna, additional, Hughes, Gareth, additional, and Critchlow, Susan E., additional

Published
2022
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6. Optimization of hERG and Pharmacokinetic Properties for Basic Dihydro-8H-purin-8-one Inhibitors of DNA-PK

Author

Goldberg, Frederick W., primary, Ting, Attilla K. T., additional, Beattie, David, additional, Lamont, Gillian M., additional, Fallan, Charlene, additional, Finlay, M. Raymond V., additional, Williamson, Beth, additional, Schimpl, Marianne, additional, Harmer, Alexander R., additional, Adeyemi, Oladipupo B., additional, Nordell, Pär, additional, Cronin, Anna S., additional, Vazquez-Chantada, Mercedes, additional, Barratt, Derek, additional, Ramos-Montoya, Antonio, additional, Cadogan, Elaine B., additional, and Davies, Barry R., additional

Published
2022
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9. The Discovery of 7-Methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor

Author

Goldberg, Frederick W., primary, Finlay, M. Raymond V., additional, Ting, Attilla K. T., additional, Beattie, David, additional, Lamont, Gillian M., additional, Fallan, Charlene, additional, Wrigley, Gail L., additional, Schimpl, Marianne, additional, Howard, Martin R., additional, Williamson, Beth, additional, Vazquez-Chantada, Mercedes, additional, Barratt, Derek G., additional, Davies, Barry R., additional, Cadogan, Elaine B., additional, Ramos-Montoya, Antonio, additional, and Dean, Emma, additional

Published
2019
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10. Discovery and In VivoEfficacy of AZ-PRMT5i-1, a Novel PRMT5 Inhibitor with High MTA Cooperativity

Author

Smith, James M., Barlaam, Bernard, Beattie, David, Bradshaw, Lauren, Chan, Ho Man, Chiarparin, Elisabetta, Collingwood, Olga, Cooke, Sophie L., Cronin, Anna, Cumming, Iain, Dean, Emma, Debreczeni, Judit É., del Barco Barrantes, Iván, Diene, Coura, Gianni, Davide, Guerot, Carine, Guo, Xiaoxiao, Guven, Sinem, Hayhow, Thomas G., Hong, Ted, Kemmitt, Paul D., Lamont, Gillian M., Lamont, Scott, Lynch, James T., McWilliams, Lisa, Moore, Shaun, Raubo, Piotr, Robb, Graeme R., Robinson, James, Scott, James S., Srinivasan, Bharath, Steward, Oliver, Stubbs, Christopher J., Syson, Karl, Tan, Lixiang, Turner, Oliver, Underwood, Elizabeth, Urosevic, Jelena, Vazquez-Chantada, Mercedes, Whittaker, Amy L., Wilson, David M., and Winter-Holt, Jon J.

Abstract

PRMT5, a type 2 arginine methyltransferase, has a critical role in regulating cell growth and survival in cancer. With the aim of developing MTA-cooperative PRMT5 inhibitors suitable for MTAP-deficient cancers, herein we report our efforts to develop novel “MTA-cooperative” compounds identified through a high-throughput biochemical screening approach. Optimization of hits was achieved through structure-based design with a focus on improvement of oral drug-like properties. Bioisosteric replacement of the original thiazole guanidine headgroup, spirocyclization of the isoindolinone amide scaffold to both configurationally and conformationally lock the bioactive form, and fine-tuning of the potency, MTA cooperativity, and DMPK properties through specific substitutions of the azaindole headgroup were conducted. We have identified an orally available in vivolead compound, 28(“AZ-PRMT5i-1”), which shows sub-10 nM PRMT5 cell potency, >50-fold MTA cooperativity, suitable DMPK properties for oral dosing, and significant PRMT5-driven in vivoefficacy in several MTAP-deficient preclinical cancer models.

Published
2024
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11. The Discovery of 7-Methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor

Author

Goldberg, Frederick W., Finlay, M. Raymond V., Ting, Attilla K. T., Beattie, David, Lamont, Gillian M., Fallan, Charlene, Wrigley, Gail L., Schimpl, Marianne, Howard, Martin R., Williamson, Beth, Vazquez-Chantada, Mercedes, Barratt, Derek G., Davies, Barry R., Cadogan, Elaine B., Ramos-Montoya, Antonio, and Dean, Emma

Abstract

DNA-PK is a key component within the DNA damage response, as it is responsible for recognizing and repairing double-strand DNA breaks (DSBs) via non-homologous end joining. Historically it has been challenging to identify inhibitors of the DNA-PK catalytic subunit (DNA-PKcs) with good selectivity versus the structurally related PI3 (lipid) and PI3K-related protein kinases. We screened our corporate collection for DNA-PKcs inhibitors with good PI3 kinase selectivity, identifying compound 1. Optimization focused on further improving selectivity while improving physical and pharmacokinetic properties, notably co-optimization of permeability and metabolic stability, to identify compound 16(AZD7648). Compound 16had no significant off-target activity in the protein kinome and only weak activity versus PI3Kα/γ lipid kinases. Monotherapy activity in murine xenograft models was observed, and regressions were observed when combined with inducers of DSBs (doxorubicin or irradiation) or PARP inhibition (olaparib). These data support progression into clinical studies (NCT03907969).

Published
2024
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15. Identification and optimisation of 7-azaindole PAK1 inhibitors with improved potency and kinase selectivity

Author

McCoull, William, primary, Hennessy, Edward J., additional, Blades, Kevin, additional, Box, Matthew R., additional, Chuaqui, Claudio, additional, Dowling, James E., additional, Davies, Christopher D., additional, Ferguson, Andrew D., additional, Goldberg, Frederick W., additional, Howe, Nicholas J., additional, Kemmitt, Paul D., additional, Lamont, Gillian M., additional, Madden, Katrina, additional, McWhirter, Claire, additional, Varnes, Jeffrey G., additional, Ward, Richard A., additional, Williams, Jason D., additional, and Yang, Bin, additional

Published
2014
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19. Abstract 4478: Discovery of AZD5363, an orally bioavailable, potent ATP-competitive inhibitor of AKT kinases

Author

Luke, Richard W., primary, Addie, Matthew, additional, Box, Matthew R., additional, Buttar, David, additional, Crafter, Claire, additional, Currie, Gordon S., additional, Cosulich, Sabina C., additional, Davies, Barry, additional, Dudley, Philippa G., additional, Greenwood, Ryan, additional, Johnson, Paul D., additional, Greenwood, Hannah, additional, Lamont, Gillian M., additional, Lane, Clare, additional, Page, Ken M., additional, Pearson, Stuart E., additional, and Ruston, Linette, additional

Published
2011
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20. Synthesis of the Novel Tetrahydropyrazolo[3,4-c]pyridin-5-one Scaffold.

Author

Howe, Nicholas J., Blades, Kevin, and Lamont, Gillian M.

Subjects
CHEMICAL synthesis, PYRAZOLES, ALKYL group, ARYL group, CHEMICAL reactions
Abstract

We report an efficient synthesis of the novel 1,4,6,7-tetrahydropyrazolo[3,4-c]pyridin-5-one scaffold with the potential for incorporation of alkyl or aryl substituents at the C-3 and N-6 positions. The route utilises a Dieckmann condensation to install the lactam ring, followed by a hydrazine cyclisation to build the fused pyrazole ring. [ABSTRACT FROM AUTHOR]

Published
2015
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21. Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRASG12Cwith Demonstrable CNS Penetration

Author

Kettle, Jason G., Bagal, Sharan K., Barratt, Derek, Bodnarchuk, Michael S., Boyd, Scott, Braybrooke, Erin, Breed, Jason, Cassar, Doyle J., Cosulich, Sabina, Davies, Michael, Davies, Nichola L., Deng, Chao, Eatherton, Andrew, Evans, Laura, Feron, Lyman J., Fillery, Shaun, Gleave, Emma S., Goldberg, Frederick W., Cortés González, Miguel A., Guerot, Carine, Haider, Afreen, Harlfinger, Stephanie, Howells, Rachel, Jackson, Anne, Johnström, Peter, Kemmitt, Paul D., Koers, Alex, Kondrashov, Mikhail, Lamont, Gillian M., Lamont, Scott, Lewis, Hilary J., Liu, Libin, Mylrea, Megan, Nash, Samuel, Niedbala, Michael J., Peter, Alison, Phillips, Christopher, Pike, Kurt, Raubo, Piotr, Robb, Graeme R., Ross, Sarah, Sanders, Matthew G., Schou, Magnus, Simpson, Iain, and Steward, Oliver

Abstract

The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14, AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRASG12Cwith an anticipated low clearance and high oral bioavailability profile in humans.

Published
2023
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22. Synthesis of Benzyl Alcohol Building Blocks Bearing an Aldehyde, Pinacol Borane or Carboxylic Acid Motif via Lithium-Bromide Exchange.

Author

Blades, Kevin, Box, Matthew R., Howe, Nick J., Kemmitt, Paul D., and Lamont, Gillian M.

Subjects
BENZYL alcohol synthesis, BORANES, CARBOXYLIC acids, LITHIATION, EXCHANGE reactions
Abstract

A range of useful disubstituted benzyl alcohol building blocks have been synthesised in multigram quantities in a lithium- bromide exchange to give aldehyde, carboxylic acid and pinacol boranes in high yields. [ABSTRACT FROM AUTHOR]

Published
2014
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23. Discovery and In Vivo Efficacy of AZ-PRMT5i-1, a Novel PRMT5 Inhibitor with High MTA Cooperativity.

Author

Smith JM, Barlaam B, Beattie D, Bradshaw L, Chan HM, Chiarparin E, Collingwood O, Cooke SL, Cronin A, Cumming I, Dean E, Debreczeni JÉ, Del Barco Barrantes I, Diene C, Gianni D, Guerot C, Guo X, Guven S, Hayhow TG, Hong T, Kemmitt PD, Lamont GM, Lamont S, Lynch JT, McWilliams L, Moore S, Raubo P, Robb GR, Robinson J, Scott JS, Srinivasan B, Steward O, Stubbs CJ, Syson K, Tan L, Turner O, Underwood E, Urosevic J, Vazquez-Chantada M, Whittaker AL, Wilson DM, and Winter-Holt JJ

Subjects
Humans, Animals, Structure-Activity Relationship, Mice, Drug Discovery, Cell Line, Tumor, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Protein-Arginine N-Methyltransferases antagonists & inhibitors, Protein-Arginine N-Methyltransferases metabolism, Enzyme Inhibitors pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors chemical synthesis
Abstract

PRMT5, a type 2 arginine methyltransferase, has a critical role in regulating cell growth and survival in cancer. With the aim of developing MTA-cooperative PRMT5 inhibitors suitable for MTAP-deficient cancers, herein we report our efforts to develop novel "MTA-cooperative" compounds identified through a high-throughput biochemical screening approach. Optimization of hits was achieved through structure-based design with a focus on improvement of oral drug-like properties. Bioisosteric replacement of the original thiazole guanidine headgroup, spirocyclization of the isoindolinone amide scaffold to both configurationally and conformationally lock the bioactive form, and fine-tuning of the potency, MTA cooperativity, and DMPK properties through specific substitutions of the azaindole headgroup were conducted. We have identified an orally available in vivo lead compound, 28 ("AZ-PRMT5i-1"), which shows sub-10 nM PRMT5 cell potency, >50-fold MTA cooperativity, suitable DMPK properties for oral dosing, and significant PRMT5-driven in vivo efficacy in several MTAP-deficient preclinical cancer models.

Published
2024
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24. Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRAS G12C with Demonstrable CNS Penetration.

Author

Kettle JG, Bagal SK, Barratt D, Bodnarchuk MS, Boyd S, Braybrooke E, Breed J, Cassar DJ, Cosulich S, Davies M, Davies NL, Deng C, Eatherton A, Evans L, Feron LJ, Fillery S, Gleave ES, Goldberg FW, Cortés González MA, Guerot C, Haider A, Harlfinger S, Howells R, Jackson A, Johnström P, Kemmitt PD, Koers A, Kondrashov M, Lamont GM, Lamont S, Lewis HJ, Liu L, Mylrea M, Nash S, Niedbala MJ, Peter A, Phillips C, Pike K, Raubo P, Robb GR, Ross S, Sanders MG, Schou M, Simpson I, and Steward O

Subjects
Animals, Humans, Proto-Oncogene Proteins p21(ras) genetics, Drug Design, Glycine therapeutic use, Mutation, Antineoplastic Agents pharmacology, Neoplasms drug therapy, Lung Neoplasms drug therapy
Abstract

The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14 , AZD4747, a clinical development candidate for the treatment of KRAS G12C -positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRAS G12C with an anticipated low clearance and high oral bioavailability profile in humans.

Published
2023
Full Text
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25. Optimization of hERG and Pharmacokinetic Properties for Basic Dihydro-8 H -purin-8-one Inhibitors of DNA-PK.

Author

Goldberg FW, Ting AKT, Beattie D, Lamont GM, Fallan C, Finlay MRV, Williamson B, Schimpl M, Harmer AR, Adeyemi OB, Nordell P, Cronin AS, Vazquez-Chantada M, Barratt D, Ramos-Montoya A, Cadogan EB, and Davies BR

Abstract

The DNA-PK complex is activated by double-strand DNA breaks and regulates the non-homologous end-joining repair pathway; thus, targeting DNA-PK by inhibiting the DNA-PK catalytic subunit (DNA-PKcs) is potentially a useful therapeutic approach for oncology. A previously reported series of neutral DNA-PKcs inhibitors were modified to incorporate a basic group, with the rationale that increasing the volume of distribution while maintaining good metabolic stability should increase the half-life. However, adding a basic group introduced hERG activity, and basic compounds with modest hERG activity (IC 50 = 10-15 μM) prolonged QTc (time from the start of the Q wave to the end of the T wave, corrected by heart rate) in an anaesthetized guinea pig cardiovascular model. Further optimization was necessary, including modulation of p K a , to identify compound 18 , which combines low hERG activity (IC 50 = 75 μM) with excellent kinome selectivity and favorable pharmacokinetic properties., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)

Published
2022
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26. The Discovery of 7-Methyl-2-[(7-methyl[1,2,4]triazolo[1,5- a ]pyridin-6-yl)amino]-9-(tetrahydro-2 H -pyran-4-yl)-7,9-dihydro-8 H -purin-8-one (AZD7648), a Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor.

Author

Goldberg FW, Finlay MRV, Ting AKT, Beattie D, Lamont GM, Fallan C, Wrigley GL, Schimpl M, Howard MR, Williamson B, Vazquez-Chantada M, Barratt DG, Davies BR, Cadogan EB, Ramos-Montoya A, and Dean E

Subjects
Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Class Ib Phosphatidylinositol 3-Kinase metabolism, Dogs, Drug Discovery, Humans, Mice, Molecular Structure, Neoplasms drug therapy, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacokinetics, Purines chemical synthesis, Purines pharmacokinetics, Pyrans chemical synthesis, Pyrans pharmacokinetics, Rats, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor antagonists & inhibitors, Structure-Activity Relationship, Triazoles chemical synthesis, Triazoles pharmacokinetics, Xenograft Model Antitumor Assays, DNA-Activated Protein Kinase antagonists & inhibitors, Protein Kinase Inhibitors therapeutic use, Purines therapeutic use, Pyrans therapeutic use, Triazoles therapeutic use
Abstract

DNA-PK is a key component within the DNA damage response, as it is responsible for recognizing and repairing double-strand DNA breaks (DSBs) via non-homologous end joining. Historically it has been challenging to identify inhibitors of the DNA-PK catalytic subunit (DNA-PKcs) with good selectivity versus the structurally related PI3 (lipid) and PI3K-related protein kinases. We screened our corporate collection for DNA-PKcs inhibitors with good PI3 kinase selectivity, identifying compound 1 . Optimization focused on further improving selectivity while improving physical and pharmacokinetic properties, notably co-optimization of permeability and metabolic stability, to identify compound 16 (AZD7648). Compound 16 had no significant off-target activity in the protein kinome and only weak activity versus PI3Kα/γ lipid kinases. Monotherapy activity in murine xenograft models was observed, and regressions were observed when combined with inducers of DSBs (doxorubicin or irradiation) or PARP inhibition (olaparib). These data support progression into clinical studies (NCT03907969).

Published
2020
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