Search

Your search keyword '"Sanders, Matthew G."' showing total 8 results
Start Over Author "Sanders, Matthew G."
8 results on '"Sanders, Matthew G."'

1. Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRASG12C

Author

Kettle, Jason G., primary, Bagal, Sharan K., additional, Bickerton, Sue, additional, Bodnarchuk, Michael S., additional, Boyd, Scott, additional, Breed, Jason, additional, Carbajo, Rodrigo J., additional, Cassar, Doyle J., additional, Chakraborty, Atanu, additional, Cosulich, Sabina, additional, Cumming, Iain, additional, Davies, Michael, additional, Davies, Nichola L., additional, Eatherton, Andrew, additional, Evans, Laura, additional, Feron, Lyman, additional, Fillery, Shaun, additional, Gleave, Emma S., additional, Goldberg, Frederick W., additional, Hanson, Lyndsey, additional, Harlfinger, Stephanie, additional, Howard, Martin, additional, Howells, Rachel, additional, Jackson, Anne, additional, Kemmitt, Paul, additional, Lamont, Gillian, additional, Lamont, Scott, additional, Lewis, Hilary J., additional, Liu, Libin, additional, Niedbala, Michael J., additional, Phillips, Christopher, additional, Polanski, Radek, additional, Raubo, Piotr, additional, Robb, Graeme, additional, Robinson, David M., additional, Ross, Sarah, additional, Sanders, Matthew G., additional, Tonge, Michael, additional, Whiteley, Rebecca, additional, Wilkinson, Stephen, additional, Yang, Junsheng, additional, and Zhang, Wenman, additional

Published
2022
Full Text
View/download PDF

2. Fragment-Based Design of a Potent MAT2a Inhibitor and in Vivo Evaluation in an MTAP Null Xenograft Model

Author

De Fusco, Claudia, primary, Schimpl, Marianne, additional, Börjesson, Ulf, additional, Cheung, Tony, additional, Collie, Iain, additional, Evans, Laura, additional, Narasimhan, Priyanka, additional, Stubbs, Christopher, additional, Vazquez-Chantada, Mercedes, additional, Wagner, David J., additional, Grondine, Michael, additional, Sanders, Matthew G., additional, Tentarelli, Sharon, additional, Underwood, Elizabeth, additional, Argyrou, Argyrides, additional, Smith, James M., additional, Lynch, James T., additional, Chiarparin, Elisabetta, additional, Robb, Graeme, additional, Bagal, Sharan K., additional, and Scott, James S., additional

Published
2021
Full Text
View/download PDF

3. Fragment-Based Design of a Potent MAT2a Inhibitor and in VivoEvaluation in an MTAP Null Xenograft Model

Author

De Fusco, Claudia, Schimpl, Marianne, Börjesson, Ulf, Cheung, Tony, Collie, Iain, Evans, Laura, Narasimhan, Priyanka, Stubbs, Christopher, Vazquez-Chantada, Mercedes, Wagner, David J., Grondine, Michael, Sanders, Matthew G., Tentarelli, Sharon, Underwood, Elizabeth, Argyrou, Argyrides, Smith, James M., Lynch, James T., Chiarparin, Elisabetta, Robb, Graeme, Bagal, Sharan K., and Scott, James S.

Abstract

MAT2a is a methionine adenosyltransferase that synthesizes the essential metabolite S-adenosylmethionine (SAM) from methionine and ATP. Tumors bearing the co-deletion of p16 and MTAP genes have been shown to be sensitive to MAT2a inhibition, making it an attractive target for treatment of MTAP-deleted cancers. A fragment-based lead generation campaign identified weak but efficient hits binding in a known allosteric site. By use of structure-guided design and systematic SAR exploration, the hits were elaborated through a merging and growing strategy into an arylquinazolinone series of potent MAT2a inhibitors. The selected in vivotool compound 28reduced SAM-dependent methylation events in cells and inhibited proliferation of MTAP-null cells in vitro. In vivostudies showed that 28was able to induce antitumor response in an MTAP knockout HCT116 xenograft model.

Published
2021
Full Text
View/download PDF

4. 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
Full Text
View/download PDF

8. 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
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results