BEZ235 (NVP-BEZ235) (Synonyms: Dactolisib)

NVP-BEZ235 is a novel therapeutic agent that targets 2 molecules in thePI3K/Akt/mTOR (phosphatidylinositol 3-kinase) pathway, PI3K and mTOR. It is an ATP-competitive pan-class I PI3K inhibitor that is effective against p110α with hotspot mutations, and likewise inhibits both mammalian target of rapamycin complex 1 (mTORC1) and mTORC2 ^[1]. NVP-BEZ235 antagonizes the PI3K/mTOR signaling pathway and induces cell-cycle arrest, autophagy, and downregulation of vascular endothelial growth factor in glioma cells. NVP-BEZ235 is also an effective radiosensitizer that inhibits ataxia telangiectasia mutated (ATM) and DNA-PK catalytic subunits (DNA-PKcs), arrests cell cycle, and induces apoptosis ^[2].

NVP-BEZ235 treated colorectal cancer (CRC) cell lines resulted in transient PI3K blockade, sustained decreases in mTORC1/mTORC2 signaling, and a corresponding decrease in cell viability (IC₅₀ = 9.0-14.3 nM) ^[3]. All cell lines with PI3K-activating mutations or Pten deletions (A2780, IGROV1, MOVCAR18, OAW42, and SKOV3) were highly sensitive to NVP-BEZ235 (IC₅₀ range 26-70 nM). In contrast, HEYC2, OV167, OV207, and OVCAR5 cells, that lack PI3K-activating mutations or Pten deletions, had an IC₅₀ ≥ 100 nM (IC₅₀ range 100-210 nM) for NVP-BEZ235. Overall, a statistically significant difference between the average NVP-BEZ235 IC₅₀ for cell lines with PI3K mutations or Pten deletions (IC₅₀ = 48.5 ± 8.1 nM) compared to cell lines that lack these mutations (IC₅₀ = 95.9 ± 18.4 nM) ^[1].

Mouse model of Alzheimer's disease (AD) that expresses a mutant amyloid-β precursor protein (T41 mice) to investigate the effects of NVP-BEZ235. Ten-months-old T41 animals were treated for 14 days with NVP-BEZ235 or vehicle via oral gavage and then submitted to social memory, open field and contextual conditioned fear tests. Hippocampal slices were prepared and Aβ1-42 content, NeuN, Iba-1, CD68 and GFAP were evaluated. Tissues were further processed to evaluate cytokines levels through cytometric bead array. The treatment with NVP-BEZ235 (5 mg/kg) reduced social memory impairment in T41 mice. The drug reduced the CD68/Iba-1 ratio in CA3 region of hippocampus. NVP-BEZ235 diminished IL-10 levels in T41 mice ^[4].

References:
[1]. C. Santiskulvong, G.E. Konecny, M. Fekete, et al. Dual targeting of phosphoinositide 3-kinase and mammalian target of rapamycin using NVP-BEZ235 as a novel therapeutic approach in human ovarian carcinoma. Clin. Cancer Res., 17 (2011), pp. 2373-2384
[2]: Wang WJ, Long LM, Yang N, et al. NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, enhances the radiosensitivity of human glioma stem cells in vitro. Acta Pharmacol Sin. 2013;34:681-690.
[3]. J. Roper, M.P. Richardson, W.V. Wang, L.G. Richard, W. Chen, E.M. Coffee, et al. The dual PI3K/mTOR inhibitor NVP-BEZ235 induces tumor regression in a genetically engineered mouse model of PIK3CA wild-type colorectal cancer. PLoS ONE, 6 (2011), p. e25132
[4]. P.M.Q. Bellozi, G.F. Gomes, L.R. de Oliveira, et al. NVP-BEZ235 (Dactolisib) has protective effects in a transgenic mouse model of Alzheimer's disease. Frontiers in Pharmacology, 10 (2019), p. 1345