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21 results on '"Knowles, Phillip P"'

2. Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors

Author

Plenker, Dennis, Riedel, Maximilian, Brägelmann, Johannes, Dammert, Marcel A, Chauhan, Rakhee, Knowles, Phillip P, Lorenz, Carina, Keul, Marina, Bührmann, Mike, Pagel, Oliver, Tischler, Verena, Scheel, Andreas H, Schütte, Daniel, Song, Yanrui, Stark, Justina, Mrugalla, Florian, Alber, Yannic, Richters, André, Engel, Julian, Leenders, Frauke, Heuckmann, Johannes M, Wolf, Jürgen, Diebold, Joachim, Pall, Georg, Peifer, Martin, Aerts, Maarten, Gevaert, Kris, Zahedi, René P, Buettner, Reinhard, Shokat, Kevan M, McDonald, Neil Q, Kast, Stefan M, Gautschi, Oliver, Thomas, Roman K, and Sos, Martin L

Subjects
Orphan Drug, Rare Diseases, Cancer, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Good Health and Well Being, Adenocarcinoma, Adenocarcinoma of Lung, Animals, Cell Line, Tumor, Cytoskeletal Proteins, Drug Resistance, Neoplasm, Gene Rearrangement, Heterocyclic Compounds, 4 or More Rings, Humans, Imidazoles, Lung Neoplasms, Mice, Mutation, NIH 3T3 Cells, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-ret, Pyridazines, Biological Sciences, Medical and Health Sciences
Abstract

Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. We provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors, such as AD80 or ponatinib, that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET-rearranged tumors. Using chemical genomics in conjunction with phosphoproteomic analyses in RET-rearranged cells, we identify the CCDC6-RETI788N mutation and drug-induced mitogen-activated protein kinase pathway reactivation as possible mechanisms by which tumors may escape the activity of RET inhibitors. Our data provide mechanistic insight into the druggability of RET kinase fusions that may be of help for the development of effective therapies targeting such tumors.

Published
2017

9. A two-site flexible clamp mechanism for RET-GDNF-GFRα1 assembly reveals both conformational adaptation and strict geometric spacing

Author

Adams, Sarah E., primary, Purkiss, Andrew G., additional, Knowles, Phillip P., additional, Nans, Andrea, additional, Briggs, David C., additional, Borg, Annabel, additional, Earl, Christopher P., additional, Goodman, Kerry M., additional, Nawrotek, Agata, additional, Borg, Aaron J., additional, McIntosh, Pauline B., additional, Houghton, Francesca M., additional, Kjær, Svend, additional, and McDonald, Neil Q., additional

Published
2020
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11. Discovery of N-Trisubstituted Pyrimidine Derivatives as Type I RET and RET Gatekeeper Mutant Inhibitors with a Novel Kinase Binding Pose

Author

Zhang, Lingtian, Moccia, Marialuisa, Briggs, David C., Bharate, Jaideep B., Lakkaniga, Naga Rajiv, Knowles, Phillip, Yan, Wei, Tran, Phuc, Kharbanda, Anupreet, Wang, Xiuqi, Leung, Yuet-Kin, Frett, Brendan, Santoro, Massimo, McDonald, Neil Q., Carlomagno, Francesca, and Li, Hong-yu

Abstract

Mutations of the rearranged during transfection (RET) kinase are frequently reported in cancer, which make it as an attractive therapeutic target. Herein, we discovered a series of N-trisubstituted pyrimidine derivatives as potent inhibitors for both wild-type (wt) RET and RETV804M, which is a resistant mutant for several FDA-approved inhibitors. The X-ray structure of a representative inhibitor with RET revealed that the compound binds in a unique pose that bifurcates beneath the P-loop and confirmed the compound as a type I inhibitor. Through the structure–activity relationship (SAR) study, compound 20was identified as a lead compound, showing potent inhibition of both RET and RETV804M. Additionally, compound 20displayed potent antiproliferative activity of CCDC6-RET-driven LC-2/ad cells. Analysis of RET phosphorylation indicated that biological activity was mediated by RET inhibition. Collectively, N-trisubstituted pyrimidine derivatives could serve as scaffolds for the discovery and development of potent inhibitors of type I RET and its gatekeeper mutant for the treatment of RET-driven cancers.

Published
2022
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12. Abstract 918: A secondaryRETmutation allosterically conferring resistance to vandetanib

Author

Nakaoku, Takashi, primary, Kohno, Takashi, additional, Araki, Mitsugu, additional, Nino, Seiji, additional, Chauhan, Rakhee, additional, Knowles, Phillip P., additional, Tsuchihara, Katsuya, additional, Matsumoto, Shingo, additional, Shimada, Yoko, additional, Mimaki, Sachiyo, additional, Ishii, Genichiro, additional, Ichikawa, Hitoshi, additional, Okuno, Yasushi, additional, Yoh, Kiyotaka, additional, McDonald, Neil Q., additional, and Goto, Koichi, additional

Published
2018
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13. A secondary RET mutation in the activation loop conferring resistance to vandetanib

Author

Nakaoku, Takashi, primary, Kohno, Takashi, additional, Araki, Mitsugu, additional, Niho, Seiji, additional, Chauhan, Rakhee, additional, Knowles, Phillip P., additional, Tsuchihara, Katsuya, additional, Matsumoto, Shingo, additional, Shimada, Yoko, additional, Mimaki, Sachiyo, additional, Ishii, Genichiro, additional, Ichikawa, Hitoshi, additional, Nagatoishi, Satoru, additional, Tsumoto, Kouhei, additional, Okuno, Yasushi, additional, Yoh, Kiyotaka, additional, McDonald, Neil Q., additional, and Goto, Koichi, additional

Published
2018
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14. A secondary RET mutation in the activation loop conferring resistance to vandetanib

Author

20283666, Nakaoku, Takashi, Kohno, Takashi, Araki, Mitsugu, Niho, Seiji, Chauhan, Rakhee, Knowles, Phillip P., Tsuchihara, Katsuya, Matsumoto, Shingo, Shimada, Yoko, Mimaki, Sachiyo, Ishii, Genichiro, Ichikawa, Hitoshi, Nagatoishi, Satoru, Tsumoto, Kouhei, Okuno, Yasushi, Yoh, Kiyotaka, McDonald, Neil Q., Goto, Koichi, 20283666, Nakaoku, Takashi, Kohno, Takashi, Araki, Mitsugu, Niho, Seiji, Chauhan, Rakhee, Knowles, Phillip P., Tsuchihara, Katsuya, Matsumoto, Shingo, Shimada, Yoko, Mimaki, Sachiyo, Ishii, Genichiro, Ichikawa, Hitoshi, Nagatoishi, Satoru, Tsumoto, Kouhei, Okuno, Yasushi, Yoh, Kiyotaka, McDonald, Neil Q., and Goto, Koichi

Abstract

Resistance to vandetanib, a type I RET kinase inhibitor, developed in a patient with metastatic lung adenocarcinoma harboring a CCDC6-RET fusion that initially exhibited a response to treatment. The resistant tumor acquired a secondary mutation resulting in a serine-to-phenylalanine substitution at codon 904 in the activation loop of the RET kinase domain. The S904F mutation confers resistance to vandetanib by increasing the ATP affinity and autophosphorylation activity of RET kinase. A reduced interaction with the drug is also observed in vitro for the S904F mutant by thermal shift assay. A crystal structure of the S904F mutant reveals a small hydrophobic core around F904 likely to enhance basal kinase activity by stabilizing an active conformer. Our findings indicate that missense mutations in the activation loop of the kinase domain are able to increase kinase activity and confer drug resistance through allosteric effects.

Published
2018

15. A secondary RET mutation in the activation loop conferring resistance to vandetanib.

Author

Takashi Nakaoku, Takashi Kohno, Mitsugu Araki, Seiji Niho, Chauhan, Rakhee, Knowles, Phillip P., Katsuya Tsuchihara, Shingo Matsumoto, Yoko Shimada, Sachiyo Mimaki, Genichiro Ishii, Hitoshi Ichikawa, Satoru Nagatoishi, Kouhei Tsumoto, Yasushi Okuno, Kiyotaka Yoh, McDonald, Neil Q., and Koichi Goto

Subjects
DRUG interactions, MISSENSE mutation, DRUG resistance, CRYSTAL structure, KINASE inhibitors
Abstract

Resistance to vandetanib, a type I RET kinase inhibitor, developed in a patient with metastatic lung adenocarcinoma harboring a CCDC6-RET fusion that initially exhibited a response to treatment. The resistant tumor acquired a secondary mutation resulting in a serine-to-phenylalanine substitution at codon 904 in the activation loop of the RET kinase domain. The S904F mutation confers resistance to vandetanib by increasing the ATP affinity and autophosphorylation activity of RET kinase. A reduced interaction with the drug is also observed in vitro for the S904F mutant by thermal shift assay. A crystal structure of the S904F mutant reveals a small hydrophobic core around F904 likely to enhance basal kinase activity by stabilizing an active conformer. Our findings indicate that missense mutations in the activation loop of the kinase domain are able to increase kinase activity and confer drug resistance through allosteric effects. [ABSTRACT FROM AUTHOR]

Published
2018
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16. Adenosine-binding motif mimicry and cellular effects of a thieno[2,3-d]pyrimidine-based chemical inhibitor of atypical protein kinase C isoenzymes

Author

Kjær, Svend, primary, Linch, Mark, additional, Purkiss, Andrew, additional, Kostelecky, Brenda, additional, Knowles, Phillip P., additional, Rosse, Carine, additional, Riou, Philippe, additional, Soudy, Christelle, additional, Kaye, Sarah, additional, Patel, Bhavisha, additional, Soriano, Erika, additional, Murray-Rust, Judith, additional, Barton, Caroline, additional, Dillon, Christian, additional, Roffey, Jon, additional, Parker, Peter J., additional, and McDonald, Neil Q., additional

Published
2013
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21. A Cancer-Associated Mutation in Atypical Protein Kinase Cι Occurs in a Substrate-Specific Recruitment Motif

Author

Linch, Mark, Sanz-Garcia, Marta, Soriano, Erika, Zhang, Yixiao, Riou, Philippe, Rosse, Carine, Cameron, Angus, Knowles, Phillip, Purkiss, Andrew, Kjaer, Svend, McDonald, Neil Q., and Parker, Peter J.

Abstract

A cancer-associated mutation in protein kinase Cι selectively disrupts epithelial polarity by inhibiting the binding of specific substrates.

Published
2013
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