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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.