BEZ235, BGT226, and BKM120

Inhibiting tumor proliferation and survival by blocking the phosphatidylinositol-3-kinase (PI3K) pathway

PI3Ks are key players in an intracellular signaling network, the so-called PI3K-PDK1-PKB pathway, which regulates cell proliferation, growth, survival, and apoptosis. A substantial number of epidemiological and experimental studies support an important role for PI3Ks in the biology of human cancer. The activation of PI3Ks and downstream effectors, including PKB (AKT) and mTOR, have been validated as an essential step for the initiation and maintenance of the tumorigenic phenotype.¹

Activation of the PI3K-PDK1-PKB pathway, via the loss of PTEN or the overexpression of some receptor tyrosine kinases (EGFR, HER-2), has been implicated in poor prognosis and survival in a number of tumor types, including breast, prostate, lung, glioblastoma, melanoma, and bladder; endometrial carcinoma; and lymphatic tumors.^1-3

Inhibition of the PI3K pathway could result in
- Increased apoptosis
- Decreased cell proliferation
- Decreased growth
- Decreased cell survival

Novartis Oncology is currently developing 2 novel oral dual PI3K/mTOR inhibitors, BEZ235 and BGT226, and one oral selective PI3K inhibitor, BKM120. In preclinical studies, all 3 compounds showed high target specificity and demonstrated antiproliferative activity against tumor cell lines in animal models of cancer.²

BEZ235, BGT226, and BKM120 are currently being investigated in Phase I clinical trials in solid tumors.

All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

1. Wymann MP, Zvelebil M, Laffargue M. Phosphoinositide 3-kinase signaling-which way to target? Trends Pharmacol Sci. 2003;24:366-376.
2. Stauffer F, Garcia-Echeverirria C, Fu ret P, et al. Biochemical, cellular, and in vivo profiling of a new PI3K inhibitor from the imidazoquinoline series [abstract]. In: American Association for Cancer Research Annual Meeting: Proceedings; 2007, Apr 14-18; Los Angeles, Calif., Philadelphia (Pa): AACR; 2007. Abstract 269.
3. Ali IU, Schriml LM, Dean M. Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. J Nat Can Inst. 1999;91:1922-1932.