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mTOR Inhibitors

Mammalian target of rapamycin (mTOR) is one such protein kinase that facilitates cell growth by stimulating the cell to traverse the G1 to S phase of the cell cycle.

Rapamycin (Sirolimus) (Synonyms Rapamune) is a macrocyclic-triene antibiotic possessing potent immunosuppressant activity. It has been found to be a useful probe for studying T-cell signal transduction. Rapamycin exerts its immunosuppressant effect only after binding to the immunophilin proteins, FKBP12. Rapamycin inhibits growth factor- and mitogen-induced stimulation of proliferation of T lymphocytes by the binding of the Rapamycin-FKBP12 complex to an effector, and arresting the G1 stage in the the G1 to S transition of the cell cycle. The effectors were identified as FRAP12, (FKBP12 Rapamycin-associated protein, TOR protein) and RAFT1 (Rapamycin and FKBP12 target). The activity of FRAP and its relationship to the signaling events have not yet been delineated. The Rapamycin-FKBP12-FRAP ternary complex (3 nM rapamycin)15 induces rapid inactivation of p70s6 kinase as well as inhibition of cyclin A, the association of cyclin A with p34cdc2, and decreased p34cdc2 and p33cdk2 activities. Rapamycin (IC50=1 nM0 inhibited human peripheral blood mononuclear cell proliferation (induced by 0.1% phytohemagglutinin) and was about 50-100 fold more potent than cyclosporin A.

Rapamycin (1.2 mm) inhibits protein kinase C activity and stimulates (10-5M – 10-6) ion transport in A6 cells.
Rapamycin inhibits the immune response in membrane and cytosolic preparations. It exhibits distinct effects
on translation of endogeneous mRNA's and it (20 nM) suppresses 5'TOP mRNA translation through the inhibition of p70s6k activation in the signaling pathway.

Rapamycin has been shown to have both antifungal (inhibits yeast and filamentous fungus) and antineoplastic properties. Rapamycin is active mainly against Candida albicans having minimum inhibitory concentrations (MIC) against various strains from 0.02-0.2 μg/ml Comparison of its activity (MIC concentration) with that of amphotericin B, nystatin and candicidin have been reported.

Rapamycin is the first defined inhibitor of mTOR, and the demonstration of its antitumor activity has led to great interest in this pathway as an antitumor mechanism. Analogues with better pharmacologic properties have been developed and have entered clinical trials. Human cell lines of renal cell cancer, among several other tumors, are sensitive to growth inhibition via this pathway. Ongoing clinical trials are evaluating renal cell cancer and other malignancies using therapy with mTOR inhibitors. These agents are more likely to induce growth inhibition rather than tumor regression.

Storage/Stability:
Rapamycin can dissolve in chloroform ( 5 mg/ml), in methanol (25 mg/ml), and in DMSO (25 mg/ml).
Rapamycin is also soluble in ethanol, ether, acetone and N,N-dimethylformamide and is substantially insoluble in water. It is very sparingly soluble in hexane and in petroleum ether. A 10 mg/ml solution in methanol (HPLC grade and degassed methanol) was kept at 2-8 °C for one week with no decomposition. A 2 mM solution in ethanol
was stored at -70°C and was diluted into a serum-free media before use. For pancreatic acini cell studies,
the final concentration of ethanol did not exceed 0.1%. Unless otherwise indicated, solutions are probably best prepared fresh and protected from light.

Rapamycin can be prepared in ethanol at 50 mg/ml as a stock solution and then formulated in a water solution containing 5% PEG-300, 4% ethanol, and 5% Tween 80 [4].

References on Rapamycin (RAPA):

[1] Janice P. Dutcher. Current Oncology Reports. 2004 April;6(2):111-115
[2] Bruce R. Blazar et al. Blood. 1994 January 15;83(2):600-609
[3] VF Quesniaux et al. Blood. 1994 September 1; 84(5) :1543-1552
[4] Nogueira de Francischi J, Conroy DM, Maghni K, Sirois P. Inhibition by rapamycin of leukocyte migration and bronchial hyperreactivity induced by injection of Sephadex beads to guinea-pigs. Br J Pharmacol. 1993, 110(4):1381-6.

AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mTOR kinase inhibitor with an IC50 of 0.8 nM. It inhibits the phosphorylation of mTORC1 substrates p70S6K and 4E-BP1 as well as phosphorylation of the mTORC2 substrate AKT and downstream proteins. The rapamycin-resistant T37/46 phosphorylation sites on 4E-BP1 were fully inhibited by AZD8055, resulting in significant inhibition of cap-dependent translation. In vitro, AZD8055 potently inhibits proliferation and induces autophagy in H838 and A549 cells. In vivo, AZD8055 induces a dose-dependent pharmacodynamic effect on phosphorylated S6 and phosphorylated AKT at plasma concentrations leading to tumor growth inhibition. [1][2]

References on AZD8055:

[1] Chresta CM et al. Cancer Res. 2010 Jan 1;70(1):288-98

[2] Sini P et al. Autophagy. 2010 May 2;6(4)

BEZ235 (NVP-BEZ235) is a dual ATP-competitive phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor with an IC50 of 4, 5, 7 and 75 nM for p110α, p110γ, p110δ and p110β, respectively. BEZ235 (NVP-BEZ235) is also a mTORC1/2 catalytic inhibitor. BEZ235 (NVP-BEZ235) significantly reduced the phosphorylation levels of the mTOR activated kinase p70S6K. BEZ235 (NVP-BEZ235) resulted in a reduction of S235/S236P-RPS6 levels with an IC50 of 6.5 nM. The activity of BEZ235 (NVP-BEZ235) against mTOR was determined using a biochemical mTOR K-LISA assay with an IC50 of 20.7 nM. BEZ235 (NVP-BEZ235) shows slightly lower activity against the β paralogue with an IC50 of 75 nM. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells. [1] BEZ235 (NVP-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 showed a dose-dependent reduction in cell proliferation when treated with increasing concentrations of BEZ235 (NVP-BEZ235), with an average GI50 of 10 to 12 nM. BEZ235 (NVP-BEZ235) even induced regression of the tumors (69%) without statistically significant effect on body weight gain. Altogether, these preliminary in vivo efficacy results show that BEZ235 (NVP-BEZ235) causes disease stasis when administered orally as a single agent and can enhance the efficacy of other anticancer agents when used in in vivo combination studies. [2]

Protocol:

Biochemical assay:
PI3Kα, β, and δ proteins were composed of the iSH2 domain of p85 NH2-terminally fused to the full-length protein p110 protein, with the exception of α that also did not contain the last 20 amino acids. PI3Kγ was produced as full-length protein deleted for its first 144 amino acids. All constructs were fused to a COOH-terminal His tag for convenient purification and then cloned into the pBlue-Bac4.5 (for α, β, and δ isoforms) or pVL1393 (for γ isoform) plasmids. The different vectors were then cotransfected with BaculoGold WT genomic DNA using methods recommended by the vendor for production of the respective recombinant baculoviruses and proteins. BEZ235 (NVP-BEZ235) were tested for their activity against PI3K using a Kinase-Glo assay. The kinase reaction was done in 384-well black plate. Each well was loaded with 50 nl of test items (in 90% DMSO) and 5 μLl reaction buffer containing 10 μg/ml PI substrate (l-α-phosphatidylinositol; Avanti Polar Lipids; prepared in 3% octyl-glucoside) and the PI3K proteins (10, 25, 10, and 150 nM of p110α, p110β, p110δ, and p110γ, respectively) were then added. The reaction was started by the addition of 5 μl of 1 μM ATP prepared in the reaction buffer and ran for either 60 (for p110α, p110β, and p110δ) or 120 min (for p110γ) and subsequently terminated by the addition of 10 μL Kinase-Glo buffer. The plates were then read in a Synergy 2 reader for luminescence detection. [2]

Cell assay:
HCT116 (PIK3CA mutant; kinase domain at H1047R), DLD-1 (PIK3CA mutant; helical domain at E545K), and SW480 (PIK3CA wild-type) human CRC cell lines (ATCC) and isogenic DLD-1 PIK3CA mutant and wild-type cells were maintained in DMEM (Invitrogen) with 10% FBS and 1× Penicillin/Streptomycin. Cells were plated at different initial densities (HCT116: 3,000 cells/well, DLD-1: 5,500 cells/well, SW480: 4,500 cells/well, DLD-1 PIK3CA mutant: 7,000 cells/well, and DLD-1 PIK3CA wild-type: 9,000 cells/well) to account for differential growth kinetics. After 16 hours, cells were incubated with increasing concentrations of BEZ235 (NVP-BEZ235), and drug-containing growth medium was changed every 24 hours. Cell viability was assessed 16 hours after the initial plating and 48 hours after initiation of drug treatment using the colorimetric MTS assay CellTiter 96® AQueous One Solution Cell Proliferation Assay, as per the manufacturer’s instructions. Cell viability after drug treatment was normalized to that of untreated cells also grown for 48 hours. IC50 values were calculated using 4 parameter nonlinear regression in GraphPad Prism 5. For western blot analysis, cells were plated with 0 nM or maximal inhibitory dose (500 nM) BEZ235 (NVP-BEZ235) for 2, 6, 24, or 48 hours. [1]

Animal study:
Comparisons between groups and vehicle cont

References on BEZ235 (NVP-BEZ235):

[1] Roper J et al. PLoS One. 2011;6(9):e25132.

[2] Maira SM et al. Mol Cancer Ther. 2008 Jul;7(7):1851-63. 

Chrysophanic acid (Chrysophanol)is a EGFR/mTOR pathway inhibitor. Chrysophanic acid (Chrysophanol) is a natural anthraquinone, has anticancer activity in EGFR-overexpressing SNU-C5 human colon cancer cells. Chrysophanic acid (Chrysophanol) preferentially blocked proliferation in SNU-C5 cells but not in other cell lines (HT7, HT29, KM12C, SW480, HCT116 and SNU-C4) with low levels of EGFR expression. Chrysophanic acid (Chrysophanol) treatment in SNU-C5 cells inhibited EGF-induced phosphorylation of EGFR and suppressed activation of downstream signaling molecules, such as AKT, extracellular signal-regulated kinase (ERK) and the mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (p70S6K). Chrysophanic acid (80 and 120 µM) significantly blocked cell proliferation when combined with the mTOR inhibitor, rapamycin. [1]

References on Chrysophanic acid (Chrysophanol):

[1] Lee MS et al. Phytother Res. 2010 Nov 19. doi: 10.1002/ptr.3323.

Deforolimus (Ridaforolimus) is a small-molecule inhibitor of mTOR. It is an immunosuppressant for the treatment of certain cancers. Blocking mTOR creates a starvation-like effect in cancer cells by interfering with cell growth, division, metabolism, and angiogenesis. [1]

References on Deforolimus (Ridaforolimus):
[1] http://en.wikipedia.org/wiki/Ridaforolimus

Everolimus (RAD001), is a 40-O-(2-hydroxyethyl) derivative of rapamycin with immunosuppressant and anti-angiogenic properties, which exhibits improved aqueous solubility relative to the parent compound for oral administration[1] . In cells, Everolimus binds to the immunophilin FK Binding Protein-12 (FKBP-12) to generate an immunosuppressive complex that binds to and inhibits the activation of mTOR. Inhibition of mTOR activation results in the inhibition of T lymphocyte activation and proliferation associated with antigen and cytokine (IL-2, IL-4, and IL-15) stimulation and the inhibition of antibody production[1,2] . RAD001 inhibits the proliferation of a wide variety of human solid tumor cell lines both in vitro in cell culture and in vivo in animal xenograft models. HONE-1 cell was most sensitive to RAD001 (IC50=0.63 nM), while Het-1A (a normal esophageal epithelial cell line) was relatively resistant[3,4] A phase I/II study was done to determine safety and efficacy of Everolimus in patients with relapsed or refractory hematologic malignancies[4] .

References on Everolimus (RAD001):

[1] Anne Boulay et al.Cancer Res.2004 January 1;64:252-261

[2] Ranjit K. Goudar et al. Mol Cancer Ther January. 2005, 4:101-112

[3] Schuler W et al. Transplantation. 1997 Jul 15;64(1):36-42

[4] Iwan Beuvink et al. Cell.2005 March 25; 120(6):747-759

GDC-0980 (RG7422) is a selective, dual PI3 Kinase and mTOR Kinase inhibitor with IC50 of 5, 27, 7, and 14 nM for PI3Kα, β, δ, and γ, respectively. [1] PI3 Kinase is an oncogene which is commonly mutated in cancer. The PI3K/Akt/mTOR signaling pathway modulates cell growth and survival and play a crucial role downsream of KIT signaling. GDC-0980 (RG7422) prevents mTOR with a Ki of 17 nM. GDC-0980 (RG7422) is highly selective versus a large panel of kinases including others in the PIKK family. GDC-0980 (RG7422) possesses robust activity and excellent pharmacokinetic and pharmaceutical properties in cancer models driven by the PI3K pathway. GDC-0980 potently prevents signal transduction downstream of both PI3K and mTOR, as measured by pharmacodynamic (PD) biomarkers, thereby acting upon two key pathway nodes to produce the strongest attainable inhibition of signaling in the pathway. Correspondingly, GDC-0980 (RG7422) was potent across a broad panel of cancer cell lines, with the greatest potency in breast, prostate, and lung cancers and less activity in melanoma and pancreatic cancers, consistent with KRAS and BRAF acting as resistance markers. Treatment of cancer cell lines with GDC-0980 resulted in G1 cell cycle arrest, and in contrast to mTOR inhibitors, Correspondingly triggered apoptosis in certain cancer cell lines, including those with direct pathway activation via PI3K and PTEN. Low doses of Correspondingly potently suppressed tumor growth in xenograft models including those with activated PI3K, loss of LKB1 or PTEN, and elicited an exposure-related decrease in PD biomarkers. On the basis of the cell potency, low clearance in mouse, and high free fraction, 2 demonstrated significant efficacy in mouse xenografts when dosed as low as 1 mg/kg orally and is currently in phase I clinical trials for cancer. [2] GDC-0980 (RG7422) is originally developed by Genentech. The phase I clinical trials for GDC0980 is currently recruiting participants.

References on GDC-0980 (RG7422):

[1] Sutherlin DP et al. J Med Chem. 2011 Nov 10;54(21):7579-87.

[2] Wallin JJ et al. Mol Cancer Ther. 2011 Oct 13.

GSK1059615 is a pan-PI3K reversible inhibitor with sub-nanomolar IC50 for PI3Kα (0.4 nM) and PI3Kβ (0.6 nM) and shows low nanomolar activity towards γ(5 nM),δ(2 nM) and mTOR(12 nM). GSK1059615 inhibits PI3K pathway in cells inducing G1 arrest, although apopto-sis was observed in a subset of cell lines. Breast tumor cells seem to be more sensitive to this compound. In xenograft mice, a complete tumor inhibition and regression were observed together with an increase in plasma insulin levels. [1]

References on GSK1059615:

[1] Amancio Carnero. Expert Opinion on Investigational Drugs.2009 September;18(9):1265-1277

GSK2126458 is a highly potent PI3K and mTOR inhibitor with an app Ki of 19 pM for PI3K. In vivo, GSK2126458 showed anti-tumor activity in both pharmacodynamic and tumor growth efficacy models. In cell, in good agreement with the inhibition of potent PI3K. GSK2126458 reduced the phosphorylated AKT, p70S6K contents in a dose and time dependent way, as well as the prevention of PRAS40 and ERK. The IC50 of GSK2126458 is 2 nM for pAKT in the HCC1954 breast carcinoma cell line. In various human tumor cells, GSK2126458 had a width of inhibitory activity for potent cell growth and induced cell death. Notably, GSK2126458 acted mainly by not induction of apoptosis but cell cycle arrest, particularly in G1-phase. [1][2]

References on GSK2126458:

[1] Leung E et al. Cancer Biol Ther. 2011 Jun 1;11(11):938-46.

[2] Schenone S et al. Curr Med Chem. 2011;18(20):2995-3014.

Ku-0063794 is a specific inhibitor of mTOR, which inhibits both mTORC1 and mTORC2 with an IC50 of approximately 10 nM, but does not suppress the activity of 76 other protein kinases or seven lipid kinases, including Class 1 PI3Ks at 1000-fold higher concentrations. Ku-0063794 is cell permeant, suppresses activation and hydrophobic motif phosphorylation of Akt, S6K and SGK. Ku-0063794 also suppressed cell growth and induced a G1-cell-cycle arrest. Ku-0063794 is a prototype of mTOR inhibitor AZD8055 currently in Phase I/II trial in Advance Solid Tumors, Lymphoma and Endometrial Carcinoma. [1]

References on KU-0063794:

[1] García-Martínez JM et al. Biochem J. 2009 Jun 12;421(1):29-42.

NU7441 is a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor with IC50 of 0.01, 1.7 and 5 μM for DNA-PK, mTOR and PI 3-K, respectively. NU7441 has less inhibitory activity against ATM and ATR (IC50 valuse>100 μM). NU7441 increased the cytotoxicity of IR and etoposide in V3-YAC cells but not in V3 cells, confirming that DNA-PKcs is the cellular target of NU7441. NU7441 alone had no effect on cell cycle distribution, but accumulation in G2/M induced by exposure to IR (2 Gy) or the topoisomerase II poisons, doxorubicin (10 nM) or etoposide (0.1 µM) was increased 1.2 to 2 fold by NU7441 in SW620 cells. [1][2]

References on NU7441:

[1] http://aacrmeetingabstracts.org/cgi/content/abstract/2005/1/1180-d

[2] Zhao Y et al. Cancer Res. 2006 May 15;66(10):5354-62.

OSI027 is a potent mammalian target of rapamycin (mTOR) kinase inhibitor. OSI027 has potential antineoplastic activity. MTOR kinase inhibitor OSI-027 binds to and inhibits both the raptor-mTOR (TOR complex 1 or TORC1) and the rictor-mTOR (TOR complex 2 or TORC2) complexes of mTOR, which may result in tumor cell apoptosis and a decrease in tumor cell proliferation. MTOR is a serine/threonine kinase that is upregulated in some tumors and plays an important role downstream in the PI3K/Akt/mTOR signaling pathway.
OSI027  acts as a potent suppressor of primitive leukemic precursors. OSI027 much more effective than rapamycin in eliciting antileukemic effects in vitro. OSI027 induces apoptosis of different types of cells transformed by the T315I-BCR-ABL mutation, which confers resistance to imatinib mesylate, nilotinib, and dasatinib. [1][2][3]

References on OSI-027:

[1] Altman JK et al. Clin Cancer Res. 2011 Mar 17.

[2] Carayol N et al. Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):

[3] Vakana E et al. Autophagy. 2010 Oct 1;6(7):966-7.

Palomid 529 (P529) is a novel potent antitumour PI3K/Akt/mTOR inhibitor with a GI50 of <35 μM in the NCI-60 cell lines panel. Palomid 529 (P529) inhibits the TORC1 and TORC2 complexes and shows both inhibition of Akt signaling and mTOR signaling similarly in tumor and vasculature. Palomid 529 (P529) inhibits tumor growth, angiogenesis, and vascular permeability. However, Palomid 529 (P529) has the additional benefit of blocking pAktS473 signaling consistent with blocking TORC2 in all cells and thus bypassing feedback loops that lead to increased Akt signaling in some tumor cells. Palomid 529 (P529) inhibited both VEGF-driven (IC50 = 20 nM) and bFGF-driven (IC50 = 30 nM) endothelial cell proliferation and retained the ability to induce endothelial cell apoptosis. In addition, Palomid 529 (P529) significantly enhanced the antiproliferative effect of radiation in prostate cancer cells (PC-3). [1][2][3]

References on Palomid 529 (P529):

[1] Diaz R et al. Br J Cancer. 2009 Mar 24;100(6):932-40.

[2] Gravina GL et al. Endocr Relat Cancer. 2011 May 6.

[3] Xue Q et al. Cancer Res. 2008 Nov 15;68(22):9551-7.

PF-04691502 is a potent and selective dual PI3K/mTOR inhibitor to phosphorylation of AKT T308 and AKT S473 with IC50 of 7.5 and 3.8 nM, respectively. PF-04691502 is an ATP-competitive inhibitor which potently inhibits recombinant class I PI3K and mTOR in biochemical assays and suppresses transformation of avian fibroblasts mediated by wild type PI3Kγ, δ or mutant PI3Kα.[1] PF-04691502 has potential antineoplastic activity. In PIK3CA-mutant and PTEN-deleted cancer cell lines, PF-04691502 decreases phosphorylation of AKT T308 and AKT S473 with IC50 ranging from 7.5 to 47 nM and from 3.8 to 20 nM respectively, and inhibits cell proliferation with IC50 ranging from 179 to 313 nM. In addition, PF-04691502 inhibits both PI3K and mTOR kinases, which may result in apoptosis and growth inhibition of cancer cells overexpressing PI3K/mTOR. PF-04691502 inhibits mTORC1 activity in cells as measured by PI3K-independent nutrient stimulated assay, with an IC50 of 32 nM and inhibits the activation of PI3K and mTOR downstream effectors including AKT, FKHRL1, PRAS40, p70S6K, 4EBP1 and S6RP. Short-term exposure to PF-04691502 predominantly inhibits PI3K, while mTOR inhibition persists for 24-48 hours. PF-04691502 causes cell cycle G1 arrest, concomitant with upregulation of p27 Kip1 and reduction of Rb. Antitumor activity is observed in U87 (PTEN null), SKOV3 (PIK3CA mutation) and gefitinib- and erlotinib-resistant NSCLC xenografts. [2] PF-04691502 is originally developed by Pfizer. PF-04691502 is under a phase II clinical trial in the treatment of endometrial neoplasms.

References on PF-04691502:

[1] Kinross KM, et al.Mol Cancer Ther. 2011;10(8):1440-9.

[2] Yuan J,et al. Mol Cancer Ther. 2011;10(11):2189-99.

PI-103 is a potent, cell-permeable, ATP-competitive PI3K family members inhibitor with IC50 of 2, 8, 20, 26, 48, 83, 88, 150 nM for DNA-PK, p110α, mTORC1, PI3-KC2β, p110δ, mTORC2, p110β, and p110γ, respectively. It shows little activity against a wide array of protein kinases at 10 mM. It blocks glioma proliferation by blocking the PI 3-K/Akt pathway in vitro and in vivo. PI-103 was essentially cytostatic for cell lines and induced cell cycle arrest in the G1 phase. In blast cells, PI-103 inhibited leukemic proliferation, the clonogenicity of leukemic progenitors and induced mitochondrial apoptosis, especially in the compartment containing leukemic stem cells. PI-103 had additive proapoptotic effects with etoposide in blast cells and in immature leukemic cells. [1][2][3]

References on PI-103:

[1] Park S et al. Leukemia. 2008 Sep; 22(9):1698-706.

[2] Knight ZA et al. Cell. 2006 May 19; 125(4):733-47.

[3] Fan QW et al. Cancer Cell. 2006 May; 9(5):341-9.

PKI-587 is a highly potent dual PI3K/mTOR kinase inhibitor with IC50 of 0.4 nM and <0.1 μM for PI3K-α and mTOR, respectively. Intravenous administration of PKI-587 exhibits excellent antitumor activity in vitro and in vivo in both subcutaneous and orthotopic xenograft tumor models. Phosphorylation of PI3K/mTOR effectors (e.g., Akt) effectively inhibited by PKI-587. And PKI-587 induced apoptosis in human tumor cell lines with elevated PI3K/mTOR signaling. In vivo, PKI-587suppressed tumor growth in breast (MDA-MB-361, BT474), colon (HCT116), lung (H1975), and glioma (U87MG) xenograft models. PKI-587 (25 mg/kg, single dose i.v.) suppressed Akt phosphorylation [at threonine(T)308 and serine(S)473] for up to 36 hours, with cleaved PARP (cPARP) evident up to 18 hours in MDA-MB-361 tumors. PKI-587 also caused regression in other tumor models, and efficacy was enhanced when given in combination with PD0325901 (MEK 1/2 inhibitor), irinotecan (topoisomerase I inhibitor), or HKI-272 (neratinib, HER2 inhibitor). [1][2]

References on PKI-587:

[1] Venkatesan AM et al. J Med Chem. 2010 Mar 25;53(6):2636-45.

[2] Mallon R et al. Clin Cancer Res. 2011 May 15;17(10):3193-203

PP242 is a novel potent and selective mTOR inhibitor with an IC50 of 8 nM. PP242 also shows residual (micromolar) activity against panel of tyrosine kinases. But PP242 was much less active against other PI3K family members with IC50 of 2, 2.2, 0.1, 1.3 and 0.41 μM for p110α, p110β, p110δ, p110γ and DNA-PK, respectively. PP242 inhibits other PI 3-Kinases only at much higher concentrations. PP242, but not rapamycin, causes death of mouse and human leukemia cells. In vivo, PP242 delays leukemia onset and augments the effects of the current front-line tyrosine kinase inhibitors more effectively than does rapamycin. PP242 was also more effective than rapamycin in achieving cytoreduction and apoptosis in multiple myeloma cells. In addition, PP242 was an effective agent against primary multiple myeloma cells in vitro and growth of 8226 cells in mice. Knockdown of the TORC2 complex protein, rictor, was deleterious to multiple myeloma cells further supporting TORC2 as the critical target for PP242. [1][2][3]

References on PP242:

[1] Apsel B et al. Nat Chem Biol. 2008 Nov;4(11):691-9.

[2] Janes MR et al. Nat Med. 2010 Feb;16(2):205-13.

[3] Hoang B et al. Blood. 2010 Nov 25;116(22):4560-8.

RAPA administration in two types of fully allogeneic BM transplantation (BMT) systems in which host T cells mediate the rejection of TCD BM grafts (DBAf1 transplanted into C57BLf6 and BALBfc transplanted into C57BLf6). In both instances, RAPA administration prevented the rejection of the donor graft, accelerated post-BMT hematopoietic recovery, and did not compromise recipient survival. [2]
In vitro, rapamycin inhibited the proliferation of primary bone marrow cells induced by IL-3, GM-CSF, KL, or a complex mixture of factors present in cell-conditioned media. Rapamycin also inhibited the multiplication of colony-forming cells in suspension cultures containing IL-3 plus interleukin-1 (IL-1) or interleukin-11 (IL-11) plus KL. [3]

References on Rapamycin (Sirolimus):

[1] Janice P. Dutcher. Current Oncology Reports. 2004 April;6(2):111-115

[2] Bruce R. Blazar et al. Blood. 1994 January 15;83(2):600-609

[3] VF Quesniaux et al. Blood. 1994 September 1; 84(5) :1543-1552

Temsirolimus (also known as CCI-779) is a recently developed mTOR inhibitor, with improved aqueous solubility and more favorable pharmaceutical properties compared with the parent compound rapamycin.
Temsirolimus has shown promising preclinical and early clinical antitumor activity and is currently in phase III clinical development for the treatment of different solid tumors, including breast cancer.

References on Temsirolimus (Torisel):

[1] http://en.wikipedia.org/wiki/Temsirolimus

WAY-600 is a potent ATP-competitive mTOR inhibitor with an IC50 of about 9 nM. It is well reported that the mammalian target of rapamycin (mTOR) is centrally involved in cell growth, metabolism, and angiogenesis. WAY-600 has significant selectivity against mTOR over phosphatidylinositol 3-kinase (PI3K) isofoms (>100-fold). WAY-600 treated HEK293 cells indicated a 50% inhibition of polysomes by way-600 compared with the 11% suppression by rapamycin. Unlike the rapalogs,WAY-600 acutely blocked mTORC2-dependent phosphorylation of AKT in vitro and in vivo. In various cancer cells,WAY-600 inhibited the mTORC1 substrate P-S6K(T389) and mTORC2 substrate P-AKT(S473) at submicromolar concentrations without significant inhibition of P-AKT(T308). [1][2]

References on WAY-600:

[1] Yu K et al. Cancer Res. 2009 Aug 1;69(15):6232-40.

[2] Liu Q et al. Drug Discov Today Ther Strateg. 2009 Summer;6(2):47-55.

WYE-125132 is a highly potent, ATP-competitive and specific mTOR kinase inhibitor with an IC50 of 0.19 nM. WYE-125132 blocked the activity of the both of mTORC1 and mTORC2 in various models of cancer in vitro and in vivo. WYE-125132 is 5,000-fold more selective than PI3Ks. Moreover, WYE-125132 completely blocked amino acid-induced phosphorylation of Maf1, just as S6K1, and 4E-BP1 via the inhibition of mTOR. WYE-132-treated MG63 markedly upregulated the Maf1 amouts in the nucleus. WYE-125132 showed a substantially more effective inhibition in many respects, including cancer cell growth and survival, protein synthesis bioenergetic metabolism, and adaptation to hypoxia by contrast with the rapalog temsirolimus/CCI-779.

References on WYE-125132:

[1] Yu K et al. Cancer Res. 2010 Jan 15;70(2):621-31.

[2] Shor B et al. J Biol Chem. 2010 May 14;285(20):15380-92. 

WYE-354,a cell-permeable pyrazolopyrimidine compound,is a potent and ATP competitive inhibitor of mTOR (IC50 = 5 nM), with significant selectivity over PI3K isofoms (>100-fold). When injected into tumor-bearing nude mice, WYE-354 inhibited mTORC1 and mTORC2 and displayed robust antitumor activity in PTEN-null tumors. [1]

References on WYE-354:

[1] Yu K et al. Cancer Res. 2009 Aug 1;69(15):6232-40

WYE-687 is a potent ATP-competitive mTOR inhibitor with an IC50 of 7 nM. It is well reported that the mammalian target of rapamycin (mTOR) is centrally involved in cell growth, metabolism, and angiogenesis. Significantly, the pyrazolopyrimidines were selective for mTOR over PI3Kα (>100-fold) and PI3Kγ (>500-fold) and were poorly active in a panel of 24 protein kinases. Unlike the rapalogs, WYE-687 acutely blocked mTORC2-dependent phosphorylation of AKT in vitro and in vivo. In various cancer cells, WYE-687 inhibited the mTORC1 substrate P-S6K(T389) and mTORC2 substrate P-AKT(S473) at submicromolar concentrations without significant inhibition of P-AKT(T308). WYE-687 was identified as an ATP-competitive, and selective inhibitor of mTOR kinase activity.  [1]

References on WYE-687:

[1] Yu K et al. Cancer Res. 2009 Aug 1;69(15):6232-40.
 

XL765 is a mixed mTOR/PI3k inhibitor with IC50 of 157, 39, 113, 9 and 43 nM for mTOR, p110α, β, γ and δ, respectively. It is an orally available small molecule that has been shown in preclinical studies to selectively inhibit the activity of phosphoinositide-3 kinase (PI3K) and mammalian target of rapamycin (mTOR). In preclinical studies, XL765 slowed tumor growth or caused tumor shrinkage in multiple preclinical cancer models, including breast, lung, ovarian, and prostate cancers, and gliomas. XL765 has also been shown to enhance the anti-tumor effects of several chemotherapeutic agents in preclinical cancer models. [1]

References on XL765:

[1] Garcia-Echeverria C et al. Oncogene. 2008 Sep 18;27(41):5511-26