Background:

BEZ235 is an imidazoquinoline derivative inhibiting both PI3K and mTOR kinases with low nanomolar IC50s. It was well tolerated in preclinical animal studies as well as in clinical trials with manageable gastrointestinal side-effects^{[1, 2]}. It competes with ATP by binding to the ATP-binding site of kinases and reversibly reduces enzyme activity, resulting in growth arrest of tumor cells in G1 phase^[1]. Besides the inhibition of cell growth, BEZ235 blocks VEGF-induced angiogenesis^[3]. It may also inhibit DNA-PKcs^[4].

BEZ235 has shown potential anti-tumor activity both in vitro and in vivo. It inhibited growth of multiple cancer cell lines independently of mutation status in PI3K pathway^[5]. In xenograft mice models, it blocked PI3K signaling and showed antitumor activity^{[1, 5]}. Combination study demonstrated that it enhances the efficacy of temozolomide^[1].

Clinical data shows anti-tumor activity of BEZ235 treatment, especially in cancer patients with deregulated PI3K signaling pathway. This compound is currently under investigation in multiple clinical trials either as monotherapy or in combination with other agents.

参考文献:
1. Maira SM, Stauffer F, Brueggen J et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 2008; 7: 1851-1863.
2. Markman B, Tabernero J, Krop I et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Ann Oncol 2012; 23: 2399-2408.
3. Schnell CR, Stauffer F, Allegrini PR et al. Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging. Cancer Res 2008; 68: 6598-6607.
4. Mukherjee B, Tomimatsu N, Amancherla K et al. The dual PI3K/mTOR inhibitor NVP-BEZ235 is a potent inhibitor of ATM- and DNA-PKCs-mediated DNA damage responses. Neoplasia 2012; 14: 34-43.
5. Serra V, Markman B, Scaltriti M et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 2008; 68: 8022-8030.