BEZ235-dual PI3K/mTOR inhibitor

by Selleckchem | Sep 15 2012

BEZ235 (NVP-BEZ235)
BEZ235 is a novel orally-bioavailable PI3-kinase inhibitor, and shows strong antiproliferative and apoptotic activity in breast cancer, prostate cancer, and myeloma cell lines. In vivo study indicates that BEZ235 produces antitumor activity in xenograft models harboring PI3K pathway alterations. In preclinical toxicology studies, BEZ235 treatment is well tolerated[1] .

MECHANISM OF ACTION

According to previous study results, the PI3K–PTEN–AKT pathway is constitutively activated in many types of both sporadic and hereditary cancer and further regulates mTOR activation. [2] Therefore, several mTOR inhibitors, such as, rapamycin and its derivatives, have been studied in preclinical and clinical trials in some tumors including renal cell carcinoma, mantle cell lymphoma, hepatocellular cancer, glioblastoma multiforme and breast cancer [2]. At present, the rapamycin derivatives temsirolimus and everolimus have been approved by the US Food and Drug Administration for the treatment of patients with renal cell carcinoma. However, the clinical study in trials using mTOR inhibitors as monotherapy only shows modest results against tumors and leads to moderate effects on patient survival [3].
The following research shows than the limited therapy effects possibly results from the negative feedback loop downstream of mTOR and the specificity of rapamycin for mTOR complex 1 (mTORC1)[4]. Therefore, inhibition of mTORC1 by rapamycin treatment leads to the overactivation of the PI3K–PTEN–AKT pathway. As a new generation of drugs, BEZ235 as well as XL765 can target both mTOR complexes (mTORC1 and mTORC2) and the PI3K pathway. BEZ235 and XL765 impairs the effect of negative feedback loop downstream of mTOR. Thus these drugs shows more effective therapy results against tumors related to PI3K–PTEN–AKT pathway in preclinical experiment. These are already in Phase I clinical trials. Further investigation is still required to explore the role and the limits of mTOR in cancer therapies.

CLINICAL APPLICATION
BEZ235 is the first PI3K inhibitor to enter clinical trials in 2006, and now already in Phase I/II clinical trials in multiple types of advanced or metastatic cancers, including breast cancer, renal cell carcinoma (RCC) and pancreatic neuroendocrine tumors. Clinical data shows that BEZ235 treatment is well tolerated, induces dose-dependent pathway inhibition in tissues, and results in anti-tumor activity, particularly in patients with PI3K pathway deregulated cancers. The main parameters includes efficacy, safety, pharmacokinetics and pharmacodynamics. Besides the monotherapy, combination study of BEZ235 and other drugs is being evaluated under clinical phase II trials in metastatic or locally advanced solid tumors. Moreover, BEZ235 is also used in Phase II Trial in patients with advanced pancreatic neuroendocrine tumors (pNET) after failure of mTOR inhibitor therapy. We will continue to follow up on the new clinical studies about BEZ235 and the related combination therapy.

REFERENCE
[1] Maira, S.M., e.a., 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] Tennant, D.A. e.a., Targeting metabolic transformation for cancer therapy. Nat Rev Cancer. 2010, 10(4):267-277.
[3] Hudes, G. e.a., Temsirolimus, interferon alpha, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 2007, 356:2271-2281.
[4] Jacinto, E. E.a., Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nature Cell Biol. 2004, 6:1122–1128.

Cat.No.	Product Name	Information
S1009	Dactolisib (BEZ235)	Dactolisib (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 in cell-free assays, respectively. Inhibits ATR with IC50 of 21 nM in 3T3^TopBP1-ER cell. Dactolisib induces autophagy and suppresses HIV-1 replication. Phase 2.
S1039	Rapamycin	Rapamycin is a specific mTOR inhibitor with IC50 of ~0.1 nM in HEK293 cells.Rapamycin binds to FKBP12 and specifically acts as an allosteric inhibitor of mTORC1. Rapamycin is an autophagy activator and an immunosuppressant.
S1044	Temsirolimus	Temsirolimus is a specific mTOR inhibitor with IC50 of 1.76 μM in a cell-free assay. Temsirolimus induces autophagy and apoptosis.
S1120	Everolimus	Everolimus is an mTOR inhibitor of FKBP12 with IC50 of 1.6-2.4 nM in a cell-free assay. Everolimus induces cell apoptosis and autophagy and inhibits tumor cells proliferation.
S1523	Voxtalisib (XL765) Analogue	Voxtalisib (SAR245409, XL765) Analogue is a dual inhibitor of mTOR/PI3K, mostly for p110γ with IC50 of 9 nM; also inhibits DNA-PK and mTOR. Phase 1/2.