BEZ235 (NVP-BEZ235)

• CAT Number: I005455
• CAS Number: 915019-65-7
• Molecular Formula: C₃₀H₂₃N₅O
• Molecular Weight: 469.55
• Purity: ≥95%
• Target: PI3K
• Solubility: DMSO: ≤ 8.75 mg/mL
• Storage: 3 years -20C powder
• IC50: 4 nM/5 nM/7 nM/75 nM/6 nM(p110α/γ/δ/β/mTOR) [1]
• InChI: InChI=1S/C30H23N5O/c1-30(2,18-31)22-9-11-23(12-10-22)35-28-24-15-19(21-14-20-6-4-5-7-25(20)32-16-21)8-13-26(24)33-17-27(28)34(3)29(35)36/h4-17H,1-3H3
• InChIKey: JOGKUKXHTYWRGZ-UHFFFAOYSA-N
• SMILES: CC(C)(C#N)C1=CC=C(C=C1)N2C3=C4C=C(C=CC4=NC=C3N(C2=O)C)C5=CC6=CC=CC=C6N=C5

BEZ235 (NVP-BEZ235) is a dual ATP-competitive PI3K and mTOR inhibitor for p110α/γ/δ/β and mTOR(p70S6K) with IC50 of 4 nM/5 nM/7 nM/75 nM/6 nM, respectively; inhibits ATR with IC50 of 21 nM; shown to be poor inhibitory to Akt and PDK1.IC50 value: 4 nM/5 nM/7 nM/75 nM/6 nM(p110α/γ/δ/β/mTOR) [1]Target: PI3K/mTORin vitro: BEZ235 significantly reduces the phosphorylation levels of the mTOR activated kinase p70S6K. BEZ235 results in a reduction of S235/S236P-RPS6 levels with IC50 of 6.5 nM. The activity of BEZ23 against mTOR is determined using a biochemical mTOR K-LISA assay with IC50 of 20.7 nM. BEZ235 shows slightly lower activity against its β paralogue with IC50 of 75 nM. The PI3K/Akt/mTOR pathway is often constitutively activated in human tumor cells. BEZ235 blocks PI3K and mTOR kinase activity by binding to the ATP-binding cleft of these enzymes. Both PTEN-null cell lines PC3M and U87MG show a dose-dependent reduction in cell proliferation when treated with increasing concentrations of BEZ235 with an average GI50 of 10-12 nM [1]. BEZ235 is an mTORC1/2 catalytic inhibitor [2].in vivo: BEZ235 induces regression of the tumors (69%) without statistically significant effect on body weight gain. Altogether, these preliminary in vivo efficacy results show that BEZ235 causes disease stasis when administered orally as a single agent and can enhance the efficacy of other anticancer agents when used in combination studies [1].

Reference

1:The effect of rapamycin, NVP-BEZ235, aspirin, and metformin on PI3K/AKT/mTOR signaling pathway of PIK3CA-related overgrowth spectrum (PROS). Suzuki Y, Enokido Y, Yamada K, Inaba M, Kuwata K, Hanada N, Morishita T, Mizuno S, Wakamatsu N.Oncotarget. 2017 May 2. doi: 10.18632/oncotarget.17566. [Epub ahead of print] PMID: 28525374 2:Retinoblastoma cells activate the AKT pathway and are vulnerable to the PI3K/mTOR inhibitor NVP-BEZ235. Xie C, Freeman MJ, Lu H, Wang X, Forster CL, Sarver AL, Hallstrom TC.Oncotarget. 2017 Apr 8. doi: 10.18632/oncotarget.16970. [Epub ahead of print] PMID: 28445155 Free Article3:Efficacy of the dual PI3K and mTOR inhibitor NVP-BEZ235 in combination with imatinib mesylate against chronic myelogenous leukemia cell lines. Xin P, Li C, Zheng Y, Peng Q, Xiao H, Huang Y, Zhu X.Drug Des Devel Ther. 2017 Apr 3;11:1115-1126. doi: 10.2147/DDDT.S132092. eCollection 2017. PMID: 28435223 Free PMC Article4:A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies. Wise-Draper TM, Moorthy G, Salkeni MA, Karim NA, Thomas HE, Mercer CA, Beg MS, O/’Gara S, Olowokure O, Fathallah H, Kozma SC, Thomas G, Rixe O, Desai P, Morris JC.Target Oncol. 2017 Mar 29. doi: 10.1007/s11523-017-0482-9. [Epub ahead of print] PMID: 28357727 5:A Phase I Study of Abiraterone Acetate Combined with BEZ235, a Dual PI3K/mTOR Inhibitor, in Metastatic Castration Resistant Prostate Cancer. Wei XX, Hsieh AC, Kim W, Friedlander T, Lin AM, Louttit M, Ryan CJ.Oncologist. 2017 May;22(5):503-e43. doi: 10.1634/theoncologist.2016-0432. Epub 2017 Mar 17. PMID: 28314838 Free PMC Article6:Phase Ib dose-finding study of abiraterone acetate plus buparlisib (BKM120) or dactolisib (BEZ235) in patients with castration-resistant prostate cancer. Massard C, Chi KN, Castellano D, de Bono J, Gravis G, Dirix L, Machiels JP, Mita A, Gonzalez BM, Turri S, Maier J, Csonka D, Chakravartty A, Fizazi K.Eur J Cancer. 2017 May;76:36-44. doi: 10.1016/j.ejca.2017.01.024. Epub 2017 Mar 20. PMID: 28282611 7:PI3K/mTOR dual inhibitor BEZ235 and histone deacetylase inhibitor Trichostatin A synergistically exert anti-tumor activity in breast cancer. Chen L, Jin T, Zhu K, Piao Y, Quan T, Quan C, Lin Z.Oncotarget. 2017 Feb 14;8(7):11937-11949. doi: 10.18632/oncotarget.14442. PMID: 28060760 Free PMC Article8:The PI3K/mTOR dual inhibitor BEZ235 suppresses proliferation and migration and reverses multidrug resistance in acute myeloid leukemia. Deng L, Jiang L, Lin XH, Tseng KF, Liu Y, Zhang X, Dong RH, Lu ZG, Wang XJ.Acta Pharmacol Sin. 2017 Mar;38(3):382-391. doi: 10.1038/aps.2016.121. Epub 2017 Jan 2. PMID: 28042875 Free PMC Article9:Dual blocking of PI3K and mTOR signaling by NVP-BEZ235 inhibits proliferation in cervical carcinoma cells and enhances therapeutic response. Xie G, Wang Z, Chen Y, Zhang S, Feng L, Meng F, Yu Z.Cancer Lett. 2017 Mar 1;388:12-20. doi: 10.1016/j.canlet.2016.11.024. Epub 2016 Nov 25. PMID: 27894954 10:Kinetic modelling of in vitro data of PI3K, mTOR1, PTEN enzymes and on-target inhibitors Rapamycin, BEZ235, and LY294002. Goltsov A, Tashkandi G, Langdon SP, Harrison DJ, Bown JL.Eur J Pharm Sci. 2017 Jan 15;97:170-181. doi: 10.1016/j.ejps.2016.11.008. Epub 2016 Nov 8. PMID: 27832967