Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor

Research output: Contribution to journalArticlepeer-review

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Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. / Finlay, M. Raymond V; Anderton, Mark; Ashton, Susan; Ballard, Peter; Bethel, Paul A.; Box, Matthew R.; Bradbury, Robert H.; Brown, Simon J.; Butterworth, Sam; Campbell, Andrew; Chorley, Christopher; Colclough, Nicola; Cross, Darren A E; Currie, Gordon S.; Grist, Matthew; Hassall, Lorraine; Hill, George B.; James, Daniel; James, Michael; Kemmitt, Paul; Klinowska, Teresa; Lamont, Gillian; Lamont, Scott G.; Martin, Nathaniel; McFarland, Heather L.; Mellor, Martine J.; Orme, Jonathon P.; Perkins, David; Perkins, Paula; Richmond, Graham; Smith, Peter; Ward, Richard A.; Waring, Michael J.; Whittaker, David; Wells, Stuart; Wrigley, Gail L.

In: Journal of Medicinal Chemistry, Vol. 57, No. 20, 01.10.2014, p. 8249-8267.

Research output: Contribution to journalArticlepeer-review

Harvard

Finlay, MRV, Anderton, M, Ashton, S, Ballard, P, Bethel, PA, Box, MR, Bradbury, RH, Brown, SJ, Butterworth, S, Campbell, A, Chorley, C, Colclough, N, Cross, DAE, Currie, GS, Grist, M, Hassall, L, Hill, GB, James, D, James, M, Kemmitt, P, Klinowska, T, Lamont, G, Lamont, SG, Martin, N, McFarland, HL, Mellor, MJ, Orme, JP, Perkins, D, Perkins, P, Richmond, G, Smith, P, Ward, RA, Waring, MJ, Whittaker, D, Wells, S & Wrigley, GL 2014, 'Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor', Journal of Medicinal Chemistry, vol. 57, no. 20, pp. 8249-8267. https://doi.org/10.1021/jm500973a

APA

Finlay, M. R. V., Anderton, M., Ashton, S., Ballard, P., Bethel, P. A., Box, M. R., Bradbury, R. H., Brown, S. J., Butterworth, S., Campbell, A., Chorley, C., Colclough, N., Cross, D. A. E., Currie, G. S., Grist, M., Hassall, L., Hill, G. B., James, D., James, M., ... Wrigley, G. L. (2014). Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. Journal of Medicinal Chemistry, 57(20), 8249-8267. https://doi.org/10.1021/jm500973a

Vancouver

Author

Finlay, M. Raymond V ; Anderton, Mark ; Ashton, Susan ; Ballard, Peter ; Bethel, Paul A. ; Box, Matthew R. ; Bradbury, Robert H. ; Brown, Simon J. ; Butterworth, Sam ; Campbell, Andrew ; Chorley, Christopher ; Colclough, Nicola ; Cross, Darren A E ; Currie, Gordon S. ; Grist, Matthew ; Hassall, Lorraine ; Hill, George B. ; James, Daniel ; James, Michael ; Kemmitt, Paul ; Klinowska, Teresa ; Lamont, Gillian ; Lamont, Scott G. ; Martin, Nathaniel ; McFarland, Heather L. ; Mellor, Martine J. ; Orme, Jonathon P. ; Perkins, David ; Perkins, Paula ; Richmond, Graham ; Smith, Peter ; Ward, Richard A. ; Waring, Michael J. ; Whittaker, David ; Wells, Stuart ; Wrigley, Gail L. / Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 20. pp. 8249-8267.

Bibtex

@article{14d30f2980484193a46266a9fd358a0c,
title = "Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor",
abstract = "Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.",
author = "Finlay, {M. Raymond V} and Mark Anderton and Susan Ashton and Peter Ballard and Bethel, {Paul A.} and Box, {Matthew R.} and Bradbury, {Robert H.} and Brown, {Simon J.} and Sam Butterworth and Andrew Campbell and Christopher Chorley and Nicola Colclough and Cross, {Darren A E} and Currie, {Gordon S.} and Matthew Grist and Lorraine Hassall and Hill, {George B.} and Daniel James and Michael James and Paul Kemmitt and Teresa Klinowska and Gillian Lamont and Lamont, {Scott G.} and Nathaniel Martin and McFarland, {Heather L.} and Mellor, {Martine J.} and Orme, {Jonathon P.} and David Perkins and Paula Perkins and Graham Richmond and Peter Smith and Ward, {Richard A.} and Waring, {Michael J.} and David Whittaker and Stuart Wells and Wrigley, {Gail L.}",
year = "2014",
month = oct,
day = "1",
doi = "10.1021/jm500973a",
language = "English",
volume = "57",
pages = "8249--8267",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "20",

}

RIS

TY - JOUR

T1 - Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor

AU - Finlay, M. Raymond V

AU - Anderton, Mark

AU - Ashton, Susan

AU - Ballard, Peter

AU - Bethel, Paul A.

AU - Box, Matthew R.

AU - Bradbury, Robert H.

AU - Brown, Simon J.

AU - Butterworth, Sam

AU - Campbell, Andrew

AU - Chorley, Christopher

AU - Colclough, Nicola

AU - Cross, Darren A E

AU - Currie, Gordon S.

AU - Grist, Matthew

AU - Hassall, Lorraine

AU - Hill, George B.

AU - James, Daniel

AU - James, Michael

AU - Kemmitt, Paul

AU - Klinowska, Teresa

AU - Lamont, Gillian

AU - Lamont, Scott G.

AU - Martin, Nathaniel

AU - McFarland, Heather L.

AU - Mellor, Martine J.

AU - Orme, Jonathon P.

AU - Perkins, David

AU - Perkins, Paula

AU - Richmond, Graham

AU - Smith, Peter

AU - Ward, Richard A.

AU - Waring, Michael J.

AU - Whittaker, David

AU - Wells, Stuart

AU - Wrigley, Gail L.

PY - 2014/10/1

Y1 - 2014/10/1

N2 - Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.

AB - Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.

UR - http://www.scopus.com/inward/record.url?scp=84908371107&partnerID=8YFLogxK

U2 - 10.1021/jm500973a

DO - 10.1021/jm500973a

M3 - Article

C2 - 25271963

AN - SCOPUS:84908371107

VL - 57

SP - 8249

EP - 8267

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 20

ER -