Discovery of AZD8931, an equipotent, reversible inhibitor of signaling by EGFR, HER2, and HER3 receptors

Bernard Barlaam; Judith Anderton; Peter Ballard; Robert H. Bradbury; Laurent F A Hennequin; D. Mark Hickinson; Jason G. Kettle; George Kirk; Teresa Klinowska; Christine Lambert-Van Der Brempt; Cath Trigwell; John Vincent; Donald Ogilvie

doi:10.1021/ml400146c

Discovery of AZD8931, an equipotent, reversible inhibitor of signaling by EGFR, HER2, and HER3 receptors

Bernard Barlaam, Judith Anderton, Peter Ballard, Robert H. Bradbury, Laurent F A Hennequin, D. Mark Hickinson, Jason G. Kettle, George Kirk, Teresa Klinowska, Christine Lambert-Van Der Brempt, Cath Trigwell, John Vincent, Donald Ogilvie

Cancer Research UK Manchester Institute

Research output: Contribution to journal › Article › peer-review

Abstract

Deregulation of HER family signaling promotes proliferation and tumor cell survival and has been described in many human cancers. Simultaneous, equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the selective EGFR or HER2 therapeutic agents are ineffective or only modestly active. We describe the discovery of AZD8931 (2), an equipotent, reversible inhibitor of EGFR-, HER2-, and HER3-mediated signaling and the structure-activity relationships within this series. Docking studies based on a model of the HER2 kinase domain helped rationalize the increased HER2 activity seen with the methyl acetamide side chain present in AZD8931. AZD8931 exhibited good pharmacokinetics in preclinical species and showed superior activity in the LoVo tumor growth efficacy model compared to close analogues. AZD8931 is currently being evaluated in human clinical trials for the treatment of cancer. © 2013 American Chemical Society.

Original language	English
Pages (from-to)	742-746
Number of pages	4
Journal	ACS Medicinal Chemistry Letters
Volume	4
Issue number	8
DOIs	https://doi.org/10.1021/ml400146c
Publication status	Published - 8 Aug 2013

Keywords

AZD8931
HER receptor family
kinase inhibitor

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/ml400146c

http://pubs.acs.org/journal/amclct

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Barlaam, B., Anderton, J., Ballard, P., Bradbury, R. H., Hennequin, L. F. A., Hickinson, D. M., Kettle, J. G., Kirk, G., Klinowska, T., Lambert-Van Der Brempt, C., Trigwell, C., Vincent, J., & Ogilvie, D. (2013). Discovery of AZD8931, an equipotent, reversible inhibitor of signaling by EGFR, HER2, and HER3 receptors. ACS Medicinal Chemistry Letters, 4(8), 742-746. https://doi.org/10.1021/ml400146c

@article{7c5b14bcdd8e41078a0944e7313b17de,

title = "Discovery of AZD8931, an equipotent, reversible inhibitor of signaling by EGFR, HER2, and HER3 receptors",

abstract = "Deregulation of HER family signaling promotes proliferation and tumor cell survival and has been described in many human cancers. Simultaneous, equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the selective EGFR or HER2 therapeutic agents are ineffective or only modestly active. We describe the discovery of AZD8931 (2), an equipotent, reversible inhibitor of EGFR-, HER2-, and HER3-mediated signaling and the structure-activity relationships within this series. Docking studies based on a model of the HER2 kinase domain helped rationalize the increased HER2 activity seen with the methyl acetamide side chain present in AZD8931. AZD8931 exhibited good pharmacokinetics in preclinical species and showed superior activity in the LoVo tumor growth efficacy model compared to close analogues. AZD8931 is currently being evaluated in human clinical trials for the treatment of cancer. {\textcopyright} 2013 American Chemical Society.",

keywords = "AZD8931, HER receptor family, kinase inhibitor",

author = "Bernard Barlaam and Judith Anderton and Peter Ballard and Bradbury, \{Robert H.\} and Hennequin, \{Laurent F A\} and Hickinson, \{D. Mark\} and Kettle, \{Jason G.\} and George Kirk and Teresa Klinowska and \{Lambert-Van Der Brempt\}, Christine and Cath Trigwell and John Vincent and Donald Ogilvie",

year = "2013",

month = aug,

day = "8",

doi = "10.1021/ml400146c",

language = "English",

volume = "4",

pages = "742--746",

journal = "ACS Medicinal Chemistry Letters",

publisher = "American Chemical Society",

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Barlaam, B, Anderton, J, Ballard, P, Bradbury, RH, Hennequin, LFA, Hickinson, DM, Kettle, JG, Kirk, G, Klinowska, T, Lambert-Van Der Brempt, C, Trigwell, C, Vincent, J & Ogilvie, D 2013, 'Discovery of AZD8931, an equipotent, reversible inhibitor of signaling by EGFR, HER2, and HER3 receptors', ACS Medicinal Chemistry Letters, vol. 4, no. 8, pp. 742-746. https://doi.org/10.1021/ml400146c

TY - JOUR

T1 - Discovery of AZD8931, an equipotent, reversible inhibitor of signaling by EGFR, HER2, and HER3 receptors

AU - Barlaam, Bernard

AU - Anderton, Judith

AU - Ballard, Peter

AU - Bradbury, Robert H.

AU - Hennequin, Laurent F A

AU - Hickinson, D. Mark

AU - Kettle, Jason G.

AU - Kirk, George

AU - Klinowska, Teresa

AU - Lambert-Van Der Brempt, Christine

AU - Trigwell, Cath

AU - Vincent, John

AU - Ogilvie, Donald

PY - 2013/8/8

Y1 - 2013/8/8

N2 - Deregulation of HER family signaling promotes proliferation and tumor cell survival and has been described in many human cancers. Simultaneous, equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the selective EGFR or HER2 therapeutic agents are ineffective or only modestly active. We describe the discovery of AZD8931 (2), an equipotent, reversible inhibitor of EGFR-, HER2-, and HER3-mediated signaling and the structure-activity relationships within this series. Docking studies based on a model of the HER2 kinase domain helped rationalize the increased HER2 activity seen with the methyl acetamide side chain present in AZD8931. AZD8931 exhibited good pharmacokinetics in preclinical species and showed superior activity in the LoVo tumor growth efficacy model compared to close analogues. AZD8931 is currently being evaluated in human clinical trials for the treatment of cancer. © 2013 American Chemical Society.

AB - Deregulation of HER family signaling promotes proliferation and tumor cell survival and has been described in many human cancers. Simultaneous, equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the selective EGFR or HER2 therapeutic agents are ineffective or only modestly active. We describe the discovery of AZD8931 (2), an equipotent, reversible inhibitor of EGFR-, HER2-, and HER3-mediated signaling and the structure-activity relationships within this series. Docking studies based on a model of the HER2 kinase domain helped rationalize the increased HER2 activity seen with the methyl acetamide side chain present in AZD8931. AZD8931 exhibited good pharmacokinetics in preclinical species and showed superior activity in the LoVo tumor growth efficacy model compared to close analogues. AZD8931 is currently being evaluated in human clinical trials for the treatment of cancer. © 2013 American Chemical Society.

KW - AZD8931

KW - HER receptor family

KW - kinase inhibitor

U2 - 10.1021/ml400146c

DO - 10.1021/ml400146c

M3 - Article

VL - 4

SP - 742

EP - 746

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 8

ER -

Discovery of AZD8931, an equipotent, reversible inhibitor of signaling by EGFR, HER2, and HER3 receptors

Abstract

Keywords

Research Beacons, Institutes and Platforms

UN SDGs

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