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 T he HER receptor family comprises four related receptor tyrosine kinases (EGFR, HER2, HER3, and HER4) and is associated with two main ligand classes:1 the first class binds to EGFR, and the second class, which includes heregulins, binds to HER3 and HER4. HER2 lacks ligand-binding capacity. Homo-and/or heterodimerization of HER receptors results in the phosphorylation of key tyrosine residues in the intracellular domain and leads to the stimulation of numerous intracellular signal transduction pathways involved in cell proliferation and survival.2,3 Deregulation of HER family signaling promotes proliferation, invasion, metastasis, angiogenesis, and tumor cell survival and has been described in many human cancers, including those of the lung, head and neck, and breast. 4,5 Therefore, the HER receptor family represents a class of rational targets for anticancer drug development, and a number of small molecules targeting EGFR and HER2 are now clinically available, including gefitinib, erlotinib, and lapatinib (Figure 1). More recently, the importance of the composition of functional HER dimeric units in tumor cell signaling has become apparent in diverse systems, modeling both liganddependent and independent drives. Careful profiling of all four HER receptors has differentiated their molecular function, 6 and HER3 has been found to have a central role in the transduction of signals to the phosphatidylinositol 3-kinase (PI3K) pathway, thus mediating cell survival signals for EGFR, HER2, and potentially HER4. 7 We hypothesized that simultaneous, equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the current HER therapeutic agents are ineffective or only modestly active.Previous projects at AstraZeneca looking for selective EGFR 8−11 or HER2 12−15 inhibitors led to several preclinical and/or clinical candidates, including gefitinib, 8 a selective EGFR kinase inhibitor. Screening our collection of EGFR kinase inhibitors for HER2 activity identified a...
