Abstract 2456: Discovery of orally active 4-amino-6-arylaminopyrimidine-5-carbaldehyde oximes with dual EGFR and HER2 inhibitory activity.

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Abstract Growth factor receptors of the ErbB family, especially ErbB1 (EGFR) and ErbB2 (HER2), have attracted considerable attention in recent years as therapeutic targets for the treatment of numerous malignancies including cancers of the lung, colon, and breast, either through blockade of the extracellular ligand binding site by monoclonal antibodies (e.g. anti-EGFR antibodies cetuximab and panitumumab, and anti-HER2 antibody trastuzumab) or inhibition of the intracellular tyrosine kinase domain by small molecule inhibitors (e.g. EGFR kinase inhibitors gefitinib and erlotinib, and dual EGFR/HER2 inhibitor lapatinib). The abundance of small molecule kinase inhibitors in clinical development or on the market attests to the acceptance of ErbB inhibition as a clinically relevant paradigm. Nevertheless, the emergence of resistance mechanisms in ErbB driven or dependent tumors indicates that continued research is required to discover more effective drugs. We previously reported the discovery of JNJ-28871063, a potent inhibitor of EGFR and HER2 kinases in vitro that also showed excellent antitumor efficacy in EGFR (A431 epidermoid carcinoma) and HER2 (N87 gastric carcinoma) overexpressing xenograft models and significant extension of survival in a mouse intracranial tumor model. This compound is a 4-amino-6-arylaminopyrimidine-5-carbaldehyde oxime, a monocyclic chemotype that mimics the traditional bicyclic quinazoline scaffold via an intramolecular hydrogen-bonded pseudocycle involving the adjacent 4-amino and 5-oximino groups. In this study, we present results of a structure-guided analog program designed to optimize in vitro kinase potency and in vivo antitumor efficacy of the pyrimidine-oximes. While substituents on the 6-arylamino group are critical for ErbB inhibitory potency and kinase selectivity, substitution on the oxime oxygen may be changed to modify physico-chemical properties and bioavailability. We will discuss structure-activity relationships for the 5-oximino and 6-arylamino groups as well as the important role played by O-aminoalkyl oxime substituents in improving in vivo activity. Citation Format: Peter J. Connolly, Mary Adams, Amanda K. Beck, Stuart L. Emanuel, Angel R. Fuentes-Pesquera, Lee M. Greenberger, Robert H. Gruninger, Terry V. Hughes, Stephen A. Middleton, Sandra Moreno-Mazza, Niranjan Pandey, Steven K. Wetter, Guozhang Xu. Discovery of orally active 4-amino-6-arylaminopyrimidine-5-carbaldehyde oximes with dual EGFR and HER2 inhibitory activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2456. doi:10.1158/1538-7445.AM2013-2456

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