Abstract #3737: A highly potent, selective and orally available ALK inhibitor with demonstrated antitumor efficacy in ALK dependent lymphoma and non small cell lung cancer models
Authors: Elena Ardini, Maria Menichincheri, Cristina De Ponti, Nadia Amboldi, Dario Ballinari, Maria Beatrice Saccardo, Valter Croci, Fabio Stellari, Gemma Texido, Paolo Orsini, Ettore Perrone, Tiziano Bandiera, Andrea Lombardi Borgia, Jaqueline Lansen, Antonella Isacchi, Francesco Colotta, Enrico Pesenti, Paola Magnaghi, Arturo Galvani
Journal: Cancer Research (2009)

The chromosomal translocation t(2;5)(p23;q35) results in the expression of a constitutively active NPM-ALK fusion protein that represents the driving force for survival and proliferation of a subset of Anaplastic Large Cell Lymphoma. More recently an additional chromosomal rearrangement involving ALK has been identified in a subset of Non Small Cell Lung cancer patients. As for NPM-ALK, this new fusion variant, EML4-ALK, has a constitutively active ALK kinase activity and was demonstrated to have a strong oncogenic potential. Taken together these findings support the hypothesis that ALK represents an innovative and valuable target for cancer therapy both in ALCL and NSCL cancer patients. Here we report the identification and the preclinical characterization of NMS-E628, an orally available small-molecule inhibitor of ALK. Biochemical characterization revealed that the compound is highly potent and selective for ALK across a panel of several kinases. NMS-E628 selectively blocks proliferation of ALK-dependent cell lines with IC50s below 100 nM, concomitant with sustained inhibition of ALK phosphorylation, as well as that of its downstream pathway transducers. In vivo, NMS-E628 induced complete tumor regression when administered orally for ten consecutive days to SCID mice bearing Karpas-299 or SR-786 xenografts, with ex vivo analyses demonstrating dose-dependent target modulation that was maintained for up to 18 hours after single treatment. NMS-E628 was also highly efficacious in blocking the disseminated growth of luciferized Karpas-299 cells, as well as in a transgenic mouse leukemia model in which human NPM-ALK expression was targeted to T cells. In this latter model, which faithfully recapitulates pathological features of human ALCL, treatment of NPM-ALK transgenic mice with NMS-E628 for as little as 3 consecutive days induced complete regression as demonstrated by MRI analysis. Finally, NMS-E628 was also highly efficacious in inhibiting the in vitro and in vivo growth of the NSCLC cell line NCI-H2228, which bears the EML4-ALK rearrangement. Also in this model tumor growth inhibition was accompanied by dose-dependent inhibition of ALK phosphorylation and downstream effectors activation. These data demonstrate that this cell line is clearly dependent upon ALK for proliferation and survival and support the hypothesis that ALK inhibition may represent an effective and innovative therapy for NSCLC patients whose tumors harbour EML4-ALK. The excellent activity profile, together with the favourable pharmacokinetic and toxicological properties of NMS-E628, support the candidature of this compound for clinical development in patients with ALK-dependent malignancies.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3737.