Discovery of Pyrazolimidazopyridine Compounds As Potent in Vitro and in Vivo Anaplastic Lymphoma Kinase Inhibitors

Abstract Translocations linking anaplastic lymphoma kinase (ALK) to multiple fusion partners were identified in anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumors, esophageal squamous cell carcinomas, neuroblastoma, and in non small cell lung cancer (NSCLC). This fusion leads to constitutive activation of ALK and has potent transforming activity. The recent approval of Crizotinib validated clinically the usefulness of treating EML4-ALK +ve patients with an Alk inhibitor. We report two novel series of compounds that potently inhibit ALK both in vitro and in vivo. Two series of pyrazolimidazolpyridine compounds, with good physical properties, were identified as part of our screening effort as potent ALK inhibitors in ALK enzyme assays. Subsequent testing of the mode of action of these compounds in Del cell lines containing NPM-ALK fusions demonstrated strong inhibition of phospho-ALK. In vivo, oral administration of 10 mg/kg of a pyrazolimidazopyridine compound in a Del xenograft model in SCID mice resulted in greater than 90% inhibition of phospho-ALK over 6 hours. In conclusion, we have identified two series of pyrazolimidazopyridine compounds as potent ALK inhibitors both in vitro and in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2916. doi:1538-7445.AM2012-2916