2. Academic Validation
  3. Discovery of AZD8931, an Equipotent, Reversible Inhibitor of Signaling by EGFR, HER2, and HER3 Receptors

Discovery of AZD8931, an Equipotent, Reversible Inhibitor of Signaling by EGFR, HER2, and HER3 Receptors

  • ACS Med Chem Lett. 2013 May 31;4(8):742-6. doi: 10.1021/ml400146c.
Bernard Barlaam 1,  Judith Anderton 2,  Peter Ballard 2,  Robert H Bradbury 2,  Laurent F A Hennequin 1,  D Mark Hickinson 2,  Jason G Kettle 2,  George Kirk 2,  Teresa Klinowska 2,  Christine Lambert-van der Brempt 1,  Cath Trigwell 2,  John Vincent 2,  Donald Ogilvie 2
Affiliations

Affiliations

  • 1 Centre de Recherches, AstraZeneca , Z.I. La Pompelle, B.P. 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France.
  • 2 Oncology iMed, AstraZeneca , Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
PMID: 24900741 DOI: 10.1021/ml400146c
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.

Keywords

AZD8931; HER receptor family; kinase inhibitor.

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