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.