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INHIBITION OF mTOR FOR CANCER THERAPEUTICS

SIGNALLING BY mTOR:
A serine/threonine kinase protein named as mTOR stands for the “mammalian target of Rapamycin”. It is also known as FRAP1 that is a FK506-binding protein 12 - rapamycin associated protein-1. FRAP1 is the gene that is responsible of encoding this protein. mTOR protein is involved in many processes in the cell like cell survival, cell growth and proliferation, migration of proteins and the transcriptional regulation of cell. The mTOR regulatory proteins regulate these processes in response to the nutrient and energy status of the cell. mTOR can be an attractive target for the cancer therapy due to its active role in the different cellular processes like growth, proliferation and survival of the cell. Hence some specific mtorc2 inhibitors are synthesized that have the capability of controlling the cancer development and progression by inhibiting the functions performed by mTOR proteins [1]. So by inhibiting the mTOR signaling pathway we can control the growth of tumor and check the tumorigenesis [2].


mTOR INHIBITORS: MODE OF ACTION
Various inhibitor molecules are developed and practiced to find the best and effective inhibition of mTOR. Some relevant dosages were adjusted for the inhibitor drug at the clinical level [3]. Agonists and antagonists of mTOR proteins are utilized for the better understanding of mTOR cascade and devising the best strategy for the inhibition of mTOR. Different mTOR assays like homogenous flourogenic assays, which are adapted for the assessment of level of expression and activity of the target molecule in different kinds of systems. Kits can also be utilized as a source of convenience and increment in the sensitivity for the mTOR activity assay. A protein kinase inhibitor named Rapamycin, is an example important example of mTOR inhibitors and is also used to name this complex system of enzymatic proteins [4]. Researchers and doctors can buy mTOR inhibiting drugs for pre-clinical assessment of different drugs. When against the human models of breast and pancreatic cancers, CCI-779 was used; it gave very promising and strong inhibition [5-6]. Another drug named RAD001 was found to directly inhibit p21 gene for the inhibition of mTOR signaling pathway hence leading to the apoptosis in the cells [7]. Ku-0063794 is another recently designed and analyzed mTOR inhibitor [8].


mTOR INHIBITORS: CLINICAL TRIALS
Different mTOR inhibitors are being used against various kinds of cancers to assess their activity in the preclinical trial that further encourages it for the clinical studies [9]. Everolimus or RAD001 when used in the phase I clinical trial against the breast carcinoma patients of advanced stage gave promising results especially when used in a combinational therapy with the Letrozole [10]. This drug was also seen very effective when used alone for the treatment of renal cell carcinoma in phase II clinical studies [11]. Temsirolimus is another drug named also as CCI-779 gave very remarkable results against the metastatic or locally advanced breast cancer [12]. Recently designed FRAP1 inhibitor includes WYE-687, WYE-354 and WAY-600 which are all pyrazolopyrimidine that means an ATP competitor. Some of the clinical and preclinical trials related to these inhibitors are still in process and are near completion [13]. A combinational therapy can also be used with these inhibitors for instance NVP-BEZ235 can be used along with some other mTOR inhibitors or other inhibitors. This gave very efficient and synergistic results. The use of Rapamycin along with RTK inhibitor is an example of prostate cancer therapy [15].


REFERNCES:
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.
 

Related Products

Cat.No. Product Name Information Publications Customer Product Validation
S1044 Temsirolimus (CCI-779, NSC 683864) Temsirolimus (CCI-779, NSC 683864) is a specific mTOR inhibitor with IC50 of 1.76 μM in a cell-free assay. (26) (4)
S1120 Everolimus (RAD001) Everolimus (RAD001) is an mTOR inhibitor of FKBP12 with IC50 of 1.6-2.4 nM in a cell-free assay. (98) (7)
S1226 KU-0063794 KU-0063794 is a potent and highly specific dual-mTOR inhibitor of mTORC1 and mTORC2 with IC50 of ~10 nM in cell-free assays; no effect on PI3Ks. (19) (4)
S1235 Letrozole Letrozole is a third generation inhibitor of aromatase with IC50 of 0.07-20 nM in cell-free assays.It has no effect on the plasma levels of 17α-OH progesterone, thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), or androstenedione and does not affect normal urine electrolyte excretion or thyroid function in clinical studies. (13) (5)
S2668 WYE-687 WYE-687 is an ATP-competitive and selective inhibitor of mTOR with IC50 of 7 nM; blocks mTORC1/pS6K(T389) and mTORC2/P-AKT(S473) but no effect observed on P-AKT(T308). Selectivity for mTOR is greater than PI3Kα (>100-fold) and PI3Kγ (>500-fold). (1) (1)
S1266 WYE-354 WYE-354 is a potent, specific and ATP-competitive inhibitor of mTOR with IC50 of 5 nM, blocks mTORC1/P-S6K(T389) and mTORC2/P-AKT(S473) not P-AKT(T308), selective for mTOR than PI3Kα (>100-fold) and PI3Kγ (>500-fold). (8) (5)
S2689 WAY-600 WAY-600 is a potent, ATP-competitive and selective inhibitor of mTOR with IC50 of 9 nM; blocks mTORC1/P-S6K(T389) and mTORC2/P-AKT(S473) but not P-AKT(T308); selective for mTOR than PI3Kα (>100-fold) and PI3Kγ (>500-fold). (1) (1)
S1009 Dactolisib (BEZ235, NVP-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 3T3TopBP1-ER cell. (170) (11)

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