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.
authors.affiliation: Centre de Recherches, AstraZeneca , Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Barlaam
authors.affiliation: Oncology iMed, AstraZeneca , Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Judith
authors.initials: J
authors.lastname: Anderton
authors.affiliation: Oncology iMed, AstraZeneca , Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Ballard
authors.affiliation: Oncology iMed, AstraZeneca , Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bradbury
authors.affiliation: Centre de Recherches, AstraZeneca , Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France.
authors.forename: Laurent F A
authors.initials: LF
authors.lastname: Hennequin
authors.affiliation: Oncology iMed, AstraZeneca , Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: D Mark
authors.initials: DM
authors.lastname: Hickinson
authors.affiliation: Oncology iMed, AstraZeneca , Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Jason G
authors.initials: JG
authors.lastname: Kettle
authors.affiliation: Oncology iMed, AstraZeneca , Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: Kirk
authors.affiliation: Oncology iMed, AstraZeneca , Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Teresa
authors.initials: T
authors.lastname: Klinowska
authors.affiliation: Centre de Recherches, AstraZeneca , Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Lambert-van der Brempt
authors.affiliation: Oncology iMed, AstraZeneca , Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Cath
authors.initials: C
authors.lastname: Trigwell
authors.affiliation: Oncology iMed, AstraZeneca , Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Vincent
authors.affiliation: Oncology iMed, AstraZeneca , Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Donald
authors.initials: D
authors.lastname: Ogilvie
keywords: AZD8931; HER receptor family; kinase inhibitor