Identification and development of NVP-BEZ235 - a dual PI3K/mTOR inhibitor in Phase I clinical trials
Carlos Garcia-Echeverria
Novartis Institutes for Biomedical Research, Basel, Switzerland
The PI3K/PKB/mTOR pathway is frequently constitutively activated in human cancers through activating mutations in the PIK3CA gene and in upstream receptor tyrosine kinases, and through inactivating mutations in the tumor suppressor genes PTEN, TSC1, TSC2 and LKB1. The high frequency of such genetic alterations has made targeting components of the pathway including PI3K, PDK1, PKB and mTOR a high priority in academic and industrial laboratories and, recently, the first set of PI3K inhibitors have entered phase I clinical trials. NVP-BEZ235 is an imidazoquinoline dual PI3K/mTOR inhibitor which blocks the enzymatic activity of these enzymes in biochemical and cellular settings with IC50 values in the low nM range. The compound exhibits potent antiproliferative activity against a broad panel of tumour cell lines (GI50= 172 – 7 nM) by specifically blocking the biological function of PI3K signaling components. The activity of NVP-BEZ235 in cellular settings translates well in in vivo models of human cancer. Thus, the compound was well tolerated and displayed disease statis or tumour regression when administered orally, and enhanced the efficacy of other anticancer agents when used in in vivo combination studies In addition, to anti-tumor activity in xenograft and primary tumor models, NVP-BEZ235 has significant anti-angiogenic properties. Recently, NVP-BEZ235 entered phase I clinical trials where to date the drug has been well tolerated. Prolonged stable disease has been seen in a number of patients including two patients harboring mutations in the PIK3CA gene.
