909863-42-9Relevant articles and documents
Discovery of AZD8931, an equipotent, reversible inhibitor of signaling by EGFR, HER2, and HER3 receptors
Barlaam, Bernard,Anderton, Judith,Ballard, Peter,Bradbury, Robert H.,Hennequin, Laurent F. A.,Hickinson, D. Mark,Kettle, Jason G.,Kirk, George,Klinowska, Teresa,Lambert-Van Der Brempt, Christine,Trigwell, Cath,Vincent, John,Ogilvie, Donald
supporting information, p. 742 - 746 (2013/09/02)
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.
Inhibitors of epidermal growth factor receptor tyrosine kinase: Optimisation of potency and in vivo pharmacokinetics
Ballard, Peter,Bradbury, Robert H.,Harris, Craig S.,Hennequin, Laurent F.A.,Hickinson, Mark,Kettle, Jason G.,Kendrew, Jane,Klinowska, Teresa,Ogilvie, Donald J.,Pearson, Stuart E.,Williams, Emma J.,Wilson, Ingrid
, p. 4908 - 4912 (2008/09/21)
The structure-activity and structure-property relationships of anilinoquinazoline inhibitors of EGFR were investigated. Strategies to lower volume of distribution and shorten half-life through structure and pKa modulation are discussed.
