Abstract 1788: Preclinical development of a selective, potent small molecule ALK inhibitor

Abstract A chromosomal inversion [inv (2)(p21p23)] resulting in the expression of an oncogenic kinase fusion protein known as EML4-ALK [echinoderm microtubule-associated protein-like 4- anaplastic lymphoma kinase] has been implicated in the pathogenesis of a subset of lung adenocarcinomas. An agent (PF-02341066), originally described as a MET tyrosine kinase inhibitor (TKI) but with “off-target” ALK activity, has demonstrated significant activity in ALK-fusion positive lung cancer patients and is currently in phase II/III clinical trials. In this study, we describe the development and characterization of a novel and highly selective ALK TKI. X-276 (racemic mixture) is an orally bioavailable ATP mimetic that has high selectivity for ALK as assessed by Ambit assays (binding constant 2nM). Treatment of H3122 lung adenocarcinoma cells, which harbor the EML4-ALK E13;A20 fusion product, resulted in potent inhibition of cell growth with an IC50 of 10nM, approximately 10 fold less than the IC50 of H3122 cells treated with a racemic mixture of PF-02341066. Immunoblot analysis confirmed that X-276 inhibited ALK phosphorylation in H3122 cells. Importantly, the IC50 of X-276 in H1993 lung cancer cells, known to be MET-dependent, was >100 fold higher. In addition, the selectivity index of H3122 cells vs. hepatocyte HepG2 cells was >135. Finally, compared to vehicle controls, X-276 delayed the growth of H3122 xenografts in established nude mice by >60%. Collectively, these data show that TKIs can be developed with greater specificity against ALK. Such compounds may lead to the development of ‘second-generation’ ALK TKIs with more potency against ALK-mutant cancers. Future studies will focus on determining the mechanism of acquired resistance to ALK TKIs using these more potent ALK inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1788.