Abstract 4497: NVP-BKM120, a novel inhibitor of phosphoinosotide 3-kinase in Phase I/II clinical trials, shows significant antitumor activity in xenograft and primary tumor models

A substantial number of epidemiological and experimental studies support an important role for PI3K in the biology of human cancer. The activation of PI3K, and its downstream effectors, has been clearly validated as an essential step for the initiation and maintenance of the tumorigenic phenotype. Parallel to the clinical development of our dual pan-PI3K/mTOR modulators (e.g., NVP-BEZ235), we continued our drug discovery activities to identify PI3K inhibitors with distinct biological and pharmacological profiles. Following a structure-based design strategy, we have identified a new clinical candidate, NVP-BKM120. This 2,6-dimorpholino pyrimidine derivative is a potent pan-PI3K (e.g., IC 50 = 35 nM, p110α) that does not significantly inhibit other protein or lipid kinases (e.g., IC 50 = 4.6 μM, mTOR). The compound exhibits potent antiproliferative activity against a broad panel of tumour cell lines by specifically blocking the biological function of PI3K signaling components (e.g. IC 50 = 93 nM S473P-Akt in Rat1-p110α cells). The activity of this pan-PI3K inhibitor in cellular settings translates well in in vivo models of human cancer. NVP-BKM120 shows good oral bioavailability in preclinical species and demonstrated significant antitumor activity (growth inhibition or regression) at tolerated doses in xenografts of diverse cancer lineage in mice and rat models. Consistent with its mechanism of action, transient increases in plasma insulin and glucose levels are observed in these studies. Analyses of tumor tissues after acute dosing or at the end of efficacy studies showed a good correlation between compound exposure, PI3K pathway blockade (reduction in P-Akt levels) and antitumor activity. Dose dependent tumor growth delay or regression is also observed in primary tumor models, and, as demonstrated previously with our dual pan-PI3K/mTOR inhibitor NVP-BEZ235, in vivo synergistic activity is observed when NVP-BKM120 is combined with a MEK inhibitor in K-Ras human cancer models. NVP-BKM120 is currently undergoing Phase I/II human clinical trials for the treatment of solid tumors and hematological malignancies. 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 4497.