mTOR INHIBITORS AND CANCER THERAPY

by Selleckchem | Jul 31 2012

mTOR SIGNALING PATHWAY:
FRAP1 or FK506-binding protein 12 - rapamycin associated protein-1 is another name of mTOR (mammalian target of rapamycin) which is a serine/threonine protein kinase and encoded by FRAP1gene in human genome. Many of the cellular processes are reported to be controlled by mTOR which is in response to nutrient and energy status, these processes includes cell proliferation, cell growth, transcriptional regulation migration of proteins and cell survival. Therefore a straight forward approach is to design mTOR inhibitors that would control the process of mTOR by inhibiting its actions in the cancer cells [1] where normal processes are aberrant. mTOR signaling pathway can be checked by these inhibitors leading to control of tumor and cell growth or limiting tumorigenesis [2].

mTOR INHIBITORS AND THEIR MODE OF ACTION:
For obtaining high level of mTOR inhibition molecules are designed to inhibit mTOR pathway at clinical levels with relevant doses [3]. The application of an mTOR agonist or mTOR antagonist is famous for the understandings of mTOR pathway with other pathways during research studies. mTOR assays are used for the assessment of activity and expression of mTOR in a given system. These assays include either homogenous flourogenic assay or kits are also sued for convenience and sensitivity for an effective mTOR assay activity. Rapamycin is the well known inhibitor which is responsible for the name of this complex enzyme system [4]. For the treatment of cancers and tumors one can easily purchase these inhibitors for the assessment at preclinical level. A strong inhibition was noted on tumor cells when CCI-779 was used on human pancreatic xenograft models [5] and also breast cancer [6]. RAD001 was reported to inhibit mTOR mechanism as p21 inhibition which resulted in apoptosis [7]. A recently studied specific inhibitor is Ku-0063794 [8].

DIFFERENT mTOR INHIBITORS AT CLINICAL LEVELS:
There are various cancers against which many of these inhibitors are used, for the assessment of these inhibitors in preclinical trials and their efficient results warranted their use in clinical trials [9]. During clinical trials phase I RAD001 or also known as Everolimus, showed excellent results in patients with advanced breast carcinomas when used with Letrozole combination [10]. It was also found as effective as a single agent when used against RCC (renal cell cancer) during a phase II clinical studies [11]. Also during phase II studies Temsirolimus or CCI-779 was administered for the treatment of metastatic or locally advanced breast cancer form and effective and promising results were discovered [12]. More recently three novel mTOR inhibitors, WYE-687, WYE-354 and WAY-600 were discovered as ATP-competitive pyrazolopyrimidine, however their preclinical and clinical studies are yet to complete [13]. The implication of dual inhibitor such as NVP-BEZ235 [14] and other mTOR inhibitor drugs are also used for a synergistic and effective results for the inhibition of other pathways as well, one of the successful example is the use of receptor tyrosine kinase inhibitor (RTK) and Rapamycin for the prostate cancer therapy [15].

REFERENCES:
1. Guertin DA, S.D., The pharmacology of mTOR inhibition. Science Signaling, 2009.
2. Carraway H, H.M., Mammalian target of rapamycin (mTOR) antagonists. Breast Cancer Res, 2004.
3. Yip CK, e.a., Structure of the Human mTOR Complex I and Its Implications for Rapamycin Inhibition. Molecular Cell, 2010.
4. Huang S, e.a., Rapamycins: mechanism of action and cellular resistance. Cancer Biol Ther, 2003.
5. Ito D, e.a., In vivo antitumor effect of the mTOR inhibitor CCI-779 and gemcitabine in xenograft models of human pancreatic cancer. International Journal of Cancer, 2006.
6. Yu K, e.a., mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer, 2001.
7. Beuvink I, e.a., The mTOR Inhibitor RAD001 Sensitizes Tumor Cells to DNA-Damaged Induced Apoptosis through Inhibition of p21 Translation. Cell, 2005.
8. Martínez JM, e.a., Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR). Biochem J., 2009.
9. Huang S, H.P., Targeting mTOR signaling for cancer therapy. Current Opinion in Pharmacology, 2003.
10. Awada A, e.a., The oral mTOR inhibitor RAD001 (everolimus) in combination with letrozole in patients with advanced breast cancer: Results of a phase I study with pharmacokinetics. European Journal of Cancer, 2008.
11. Amato RJ, e.a., A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer, 2009.
12. Chan S, e.a., Phase II Study of Temsirolimus (CCI-779), a Novel Inhibitor of mTOR, in Heavily Pretreated Patients With Locally Advanced or Metastatic Breast Cancer Journal of Clinical Oncology, 2005.
13. Yu K, e.a., Biochemical, Cellular, and In vivo Activity of Novel ATP-Competitive and Selective Inhibitors of the Mammalian Target of Rapamycin Cancer Res, 2009.
14. Serra V, e.a., NVP-BEZ235, a Dual PI3K/mTOR Inhibitor, Prevents PI3K Signaling and Inhibits the Growth of Cancer Cells with Activating PI3K Mutations Cancer RS, 2008.
15. Masiello D, e.a., Combining an mTOR Antagonist and Receptor Tyrosine Kinase Inhibitors for the Treatment of Prostate Cancer. Cancer Bio and Ther, 2007.

Cat.No.	Product Name	Information
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.
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.