NVP-BEZ 235

NVP-BEZ235 (915019-65-7) is a dual PI3K and mTOR kinase inhibitor.1It inhibits VEGF-induced proliferation and angiogenesis.2Reverses lapatinib resistance.3It induces G1 arrest and reduces cyclin D1 expression in melanoma cells with negligible apoptosis.4NVP-BEZ235 inhibits the growth of cancer cells with activating PI3K mutations.5The ability of NVP-BEZ235 to inhibit PI3K has come into question. This study also shows it to be a potent inhibitor of PRKDC (IC50 = 29 nM), ATM (IC50 = 13 nM), and ATR (IC50 = 8 nM).6Active in vivo.

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Phosphatidylinositol 3-kinase (PI3K) signaling through Akt/PKB and the mammalian target of rapamycin (mTOR) controls gene expression related to cell proliferation, differentiation, and apoptosis. Increased activity of this pathway is important in many types of cancer. NVP-BEZ235 is a potent dual inhibitor of PI3K and mTOR that is well tolerated, displays disease stasis when administered orally, and enhances the efficacy of other anticancer agents when used in in vivo combination studies. It inhibits PI3K isoforms and mutants with low nanomolar IC50 values, leading to growth arrest in the G1 phase. Through its effects on PI3K, NVP-BEZ235 inhibits VEGF-induced angiogenesis. By directly blocking cell growth and indirectly inhibiting angiogenesis, it has potential in both solid tumors and in metastatic melanoma therapy.[Cayman Chemical]

A dual ATP-competitive inhibitor of PI3K and mTOR. p110α, IC50=4 nM; p110β, IC50=75 nM; p110δ, IC50=7 nM; p110γ, IC50=5 nM.

Inhibitor of phosphatidylinositol 3-kinases, P13K and mTOR.

ChEBI: An imidazoquinoline that is 3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinoline substituted at position 1 by a 4-(1-cyanoisopropyl)phenyl group and at position 8 by a quinolin-3-yl group. A dual PI3K/mTOR inhibitor used in cancer treatment.

BEZ235 induced tumor regression (69%) without a statistically significant effect on weight gain. Taken together, these preliminary in vivo efficacy findings suggest that BEZ235 blocks disease progression when administered orally alone and enhances efficacy when combined with other anticancer drugs.

p110α

NVP-BEZ235 is a selective and potent dual inhibitor of PI3 kinase and mTOR Ser/Thr protein kinase. Research studies show that NVP-BEZ235 reversibly inhibits the catalytic activity of these kinases by competing with ATP at the ATP-binding site. Studies demonstrate that NVP-BEZ235 has anti-proliferative characteristics and induces cell cycle arrest during G0/G1 phase through inhibition of CDK4 and cyclin D3.

[1] SAUVEUR-MICHEL MAIRA. 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.[J]. Molecular Cancer Therapeutics, 2008, 7 7: 1851-1863. DOI:10.1158/1535-7163.mct-08-0017
[2] CHRISTIAN R SCHNELL. Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging.[J]. Cancer research, 2008: 6598-6607. DOI:10.1158/0008-5472.can-08-1044
[3] PIETER J A EICHHORN. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235.[J]. Cancer research, 2008, 68 22: 9221-9230. DOI:10.1158/0008-5472.can-08-1740
[4] ROMINA MARONE. Targeting melanoma with dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors.[J]. Molecular Cancer Research, 2009, 7 4: 601-613. DOI:10.1158/1541-7786.mcr-08-0366
[5] VIOLETA SERRA. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations.[J]. Cancer research, 2008: 8022-8030. DOI:10.1158/0008-5472.can-08-1385
[6] MARIA REINECKE. Chemoproteomic Selectivity Profiling of PIKK and PI3K Kinase Inhibitors[J]. ACS Chemical Biology, 2019, 14 4: 655-664. DOI:10.1021/acschembio.8b01020