PI3K Inhibitors (PI3K 抑制剂)

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PI3K Inhibitors

A-769662 is a potent, reversible AMP-activated protein kinase (AMPK) activator with an EC50 of 0.8 μM.A-769662 displays selectivity towards β1 subunit-containing heterotrimers. A-769662 not only inhibits fatty acid synthesis with an IC50 of 3.2 μM but also decreases plasma glucose and triglyceride levels in vivo. The addition of A-769662 to mouse embryonic fibroblasts or primary mouse hepatocytes stimulates phosphorylation of acetyl-CoA carboxylase (ACC), effects that are completely abolished in AMPK-alpha1(-/-)alpha2(-/-) cells but not in TAK1(-/-) mouse embryonic fibroblasts. Phosphorylation of AMPK and ACC in response to A-769662 is also abolished in isolated mouse skeletal muscle lacking LKB1, a major upstream kinase for AMPK in this tissue.[1] A-769662 directly prevents the alpha(1)-isoform of the Na(+)-K(+)-ATPase which is purified from rat and human kidney cells in vitro with IC50 of 57 μM and 220 μM, respectively. Suppression of the Na(+)-K(+)-ATPase by 100 μM ouabain decreases sodium pump activity and cell surface abundance, similar to the effect of A769662 (A 769662; A-769662), without influencing the phosphorylation of AMPK and ACC.[2]

References on A-769662:

[1] Benziane B et al. Am J Physiol Cell Physiol. 2009 Dec;297(6):C1554-66.

[2] Göransson O et al. J Biol Chem. 2007 Nov 9;282(45):32549-60.

A66 is a highly specific and selective p110α inhibitor with IC50 of 32,30 and 43 nM for p110α, p110α/E545K, p110α/H1047R, respectively. A66 S potently blocks phosphorylation of Akt/PKB in a subgroup of the cell lines tested demonstrates that some cell types are highly dependent on p110α activity. A66 is more than 100 fold less active against the other class-I PI 3-kinase isoforms and had not inhibitory activity against 200 protein kinases when tested at 10 micromolar. This makes it the most selective and specific p110alpha inhibitor available for research purposes. A66 S is more efficacious at inducing growth delay in HCT116. While A66 S did not induce tumor regression in xenograft models the ability to induce growth delay indicates p110α selective have to ability to be effective as cytostatic agents in some tumor types. [1]

References on A66:

[1] Jamieson SM et al. Biochem J. 2011 Jun 14.

Acadesine is an AMP-activated protein kinase activator which is used for the treatment of acute lymphoblastic leukemia and may have applications in treating other disorders such as diabetes. [1]

References on Acadesine:

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

AS-252424 is a potent and selective PI3k γ inhibitor with IC50 of 33 and 935 nM for PI3Kγ and PI3Kα, respectively. Phosphatidylinositol 3-kinase (PI3K) catalyzes the phosphorylation of Pl at the 3 position to produce the second messengers PtdIns-(3,4)-P2 and PtdIns-(3,4,5)-P3. AS-252424 inhibits human recombinant PI3Kβ, and δ with IC50 values of 20,000, and 20,000 nM, respectively. AS-252424 also prevents C5a-mediated phosphorylation of Akt in RAW 264.7 macrophages with an IC50 of 0.23 µM. AS-252424 inhibited neutrophil recruitment 35% at a dose of 10 mg/kg in a mouse model of peritonitis. [1][2][3]

References on AS-252424:

[1] Hennessy BT et al. Nat Rev Drug Discov. 2005 Dec;4(12):988-1004.

[2] Vivanco I et al. Nat Rev Cancer. 2002 Jul;2(7):489-501.

[3] Pomel V et al. J Med Chem. 2006 Jun 29;49(13):3857-71.

AS-604850 is a selective, ATP-competitive PI3Kγ inhibitor with IC50 of 0.25, >20, >20, and 4.5 µM for the human recombinant γ, δ, β, and α isoforms, respectively. AS-604850 shows no notable activity against a wide array of protein kinases at 1 μM. AS-604850 inhibited MCP-1-mediated monocyte chemotaxis with an IC50 value of 21 µM and reduced RANTES-induced peritoneal neutrophil recruitment in a murine model of leukocyte chemotaxis with an ED50 value of 42.4 mg/kg. [1][2]

References on AS-604850:

[1] Rameh LE et al. J Biol Chem. 1999 Mar 26;274(13):8347-50.

[2] Ohashi PS et al. Nat Med. 2005 Sep;11(9):924-5.

AS-605240 is a PI3K γ inhibitor (IC50 at 8 nM), which displays 30-fold selectivity over PI3Kδ and PI3Kβ and 7.5-fold selectivity over PI3Kα. This agent is the first examples of selective PI3K γ inhibitors, and was used to block neutrophil chemotaxis in vitro and in vivo. In passive mouse models for rheumatoid arthritis these compounds minimized progression of joint destruction. [1]

References on AS-605240:

[1] Marone R et al. Biochim Biophys Acta. 2008 Jan;1784(1):159-85

AZD6482 is a PI3Kβ inhibitor (IC50=0.021μM) used in antithrombotic therapy. This agent targets a process that is critical to pathological thrombus formation without interfering with normal haemostasis, which avoids the drawbacks of the existing anti-thrombotic therapy. This agent inhibits PI3Kβ/α/γ/δwith IC50 of 0.021, 1.4, 1.2, 0.08μM, respectively. It washed platelet aggregation with concentration at 6 nM.

References on AZD6482:

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.

BKM120 (NVP-BKM120) is a bioavailable specific oral pan-class I phosphatidylinositol 3-kinase (PI3K) kinase inhibitor. BKM120 inhibits tumor proliferation and survival by blocking the phosphatidylinositol-3-kinase (PI3K) pathway. BKM120 has shown significant cell growth inhibition and induction of apoptosis in a variety of tumor cell lines as well as in animal models. BKM120 specifically inhibits class I PIK3 in the PI3K/AKT kinase (or protein kinase B) signaling pathway in an ATP-competitive manner, thereby inhibiting the production of the secondary messenger phosphatidylinositol-3,4,5-trisphosphate and activation of the PI3K signaling pathway. This may result in inhibition of tumor cell growth and survival in susceptible tumor cell populations. Activation of the PI3K signaling pathway is frequently associated with tumorigenesis. Dysregulated PI3K signaling may contribute to tumor resistance to a variety of antineoplastic agents. [1][2][3]

References on BKM120 (NVP-BKM120):

[1] Schmidt-Kittler O et al. Oncotarget. 2010 Sep;1(5):339-48.

[2] http://clinicaltrials.gov/ct2/show/NCT01068483

[3] http://www.asco.org/ascov2/Meetings/Abstracts?vmview=abst_detail_view&confID=74abstractID=53789

References on BKM120 (NVP-BKM120):

CAL-101 is a potent PI3K p110δ inhibitor with an IC50 of 65 nM. CAL-101 blocked constitutive phosphatidylinositol-3-kinase signaling, resulting in decreased phosphorylation of Akt and other downstream effectors, an increase in poly(ADP-ribose) polymerase and caspase cleavage and an induction of apoptosis. CAL-101 has 40 to 300-fold selectivity compared to other PI3K isoforms.
In vitro studies of 0.1 to 10 µM CAL-101 showed inhibition of pAKT expression and/or apoptotic effects against primary chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) cells and against a range of leukemia and lymphoma cell lines. [1][2]

References on CAL-101:

[1] http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=34213

[2] Lannutti BJ et al. Blood. 2011 Jan 13;117(2):591-4.

CAY10505 is a potent PI3Kγ inhibitor with an IC50 of 30 nM. Phosphoinositide 3-kinase γ (PI3Kγ) is expressed primarily in hematopoietic cells and plays several important roles in immunity. CAY10505 also prevents other α, β, and δ isoforms with IC50 of 0.94, 20, and 20 μM, respectively. CAY10505 significantly inhibits only the unrelated casein kinase 2 (CK2, IC50 = 20 nM). CAY10505 also suppress the phosphorylation of the PI3K substrate PKB/Akt in murine macrophages (IC50 = 228 nM). Oral administration of CAY10505 decreases neutrophil recruitment in mice to an extent that is comparable to that observed in PI3Kγ-deficient mice. [1]

References on CAY10505:

[1] Pomel V et al. J Med Chem. 2006 Jun 29;49(13):3857-71.

CH5132799 is a novel and selective class I PI3K inhibitor with IC50 of 0.014, 0.12, 0.5, 0.036, 5.3 and 1.6 μM for PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ, PI3K C2β and mTOR, respectively. [1] Phosphatidylinositol 3-kinase (PI3K) plays crucial roles for tumor progression in the survival signaling pathway (PI3K/Akt pathway). This pathway is most commonly activated in human cancer by various factors such as frequent mutation of PI3Kα, overexpression of growth factor receptor tyrosine kinases and inactivation of the PTEN gene. CH5132799 selectively prevents class I PI3Ks, especially PI3Kα but showed less inhibition of class II PI3Ks, class III PI3K and mTOR and also no inhibitory activity (IC50 >10 μM) against 26 protein kinases. Tumors harboring PIK3CA mutations were significantly sensitive to CH5132799 in vitro and were remarkably regressed by CH5132799 in in vivo mouse xenograft models. In combination with trastuzumab, tumors disappeared in the trastuzumab-insensitive breast cancer model with the PIK3CA mutation. Moreover, CH5132799 did not reverse a negative feedback loop of PI3K/Akt/mTOR signaling and induced regression against tumors regrown after long-term mTORC1 inhibitor treatment. In human tumor cell lines with PI3K pathway activation by mutation, CH5132799 revealed potent antiproliferative activity with IC50 of 0.2, 0.032, 0.056 and 0.12μM for HCT116(CRC), KPL-4(BC), T-47D(BC) and SK-OV-3(Ovarian), respectively. CH5132799 is orally available and indicated significant antitumor activity in PI3K pathway-activated human cancer xenograft models in mice. [2]

References on CH5132799:

[1] Ohwada J et al. Bioorg Med Chem Lett. 2011 Mar 15;21(6):1767-72.

[2] Tanaka H et al. Clin Cancer Res. 2011 May 15;17(10):3272-81.

D-106669 is a highly selective PI3K inhibitor with a submicromolar inhibition. It is well docume D-106669nted that the pyridopyrazine core of D-106669 is substituted by an aniline residue, and has been the base scaffold of a more advanced derivative AEZS-126 which is also identified as a selective class I PI3K inhibitor with an IC50 of < 10nM for PI3K alpha. When was given at oral dose of 30mg/kg twice daily, D-106669 presented certain inhibitory activity in A549 xenografts mouse model.
Another optimized compound of NVP-BEZ235 is NVP-BEZ235 that is also a PI3K alpha inhibitor (IC50 =4nM) but has less suppressed PI3Kγ, β and δ. [1]

References on D-106669:

[1] Maira SM et al. Future Med Chem. 2009 Apr;1(1):137-55.

D-87503 is a potent PI3K/Akt/mTOR signaling pathway inhibitor with IC50 of 62nM and 0.76μM for PI3K and Erk2, respectively. In cellular assays, D-87503 also effectively suppressed the target downstream substrates Akt and Rsk1 kinase of the PI3K/Akt/mTOR signaling pathway. D-87503 inhibited several carcinoma cell lines, including BxPC3, Hct116, MDA-MB 468 and 231 with EC50 of median 5µM. [1]

References on D-87503:

[1] Maira SM et al. Biochem Soc Trans. 2009 Feb;37(Pt 1):265-72.

GDC-0941 against p110a IC50=0.003μM, U87MG IC50=0.95μM, A2780 IC50=0.14 μM, and in vitro metabolic stability in mouse and human is 91.96%. The inhibitions of U87MG , PC3, MDA-MB-361 cancer cell proliferation are (IC50) 0.95, 0.28, 0.72 μM, respectively.

References on GDC-0941:

[1] Adrian J. Folkes et al. J. Med. Chem.2008,51(18):5522–5532

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.

IC-87114 is the first isoform-selective PI3K inhibitor. This quinazolinone purine inhibits p110δ(IC50=0.13µM) at mid-nanomolar concentrations and shows 100–1000-fold selectivity over other class I PI3Ks (p110α, p110β and p110γ ). The selectivity of IC87114 is remarkable given that the residues that line the ATP binding pocket of the class I PI3Ks are highly conserved. [1,2]

References on IC-87114:

[1] Marone R et al. Biochim Biophys Acta. 2008 Jan;1784(1):159-85

[2] Z.A. Knight and K.M. Shokat. Biochemical Society Transactions.2007,35:245-249

[3] Kyung S. Lee et al. The FASEB Journal. 2006;20:455-465

LY 294002 has been shown to be a potent inhibitor of PI 3-kinase activity, acting as a competitive inhibitor for ATP binding site of the enzyme. LY 294002 inhibits cell proliferation of choroidal melanoma OCM-1 cells, the IC50 was observed about 10 μM, a concentration higher than, but compatible with, the one (1.4 μM) reported for in vitro inhibition of PI 3-kinase activity. [1]
LY 294002 is also an inhibitor of casein kinase II. Application of LY 294002 causes a substantial acceleration of MEPP frequency (150 μM) at the frog neuromuscular junction, through a mechanism that is independent of intraterminal calcium. LY 294002 causes the release of MEPPs through a perturbation of synaptotagmin function. [2]

References on LY294002:

[1] Fabrice Casagrande et al. FEBS Letters. 1998 February 6;422(3):385-390

[2] Searl TJ et al. Purinergic Signal. 2005 Dec;1(4):389-94

[3] Zarzyńska J, Motyl T. J Physiol Pharmacol. 2005 Jun;56(3):181-93

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.

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.

Phenformin hydrochloride is a hydrochloride salt of phenformin that is an anti-diabetic drug from the biguanide class. Phenformin is a biguanide. Phenformin can increase AMPK activity without increasing AMP/ATP. In a study, in hearts treated with phenformin for 18 min and then perfused for 20 min with Krebs-Henseleit buffer, [AMP] began to increase at 26 min and AMPK activity was elevated at 36 min. In hearts treated with metformin, [AMP] was increased at 50 min and AMPK activity, phosphorylated AMPK, and phosphorylated acetyl-CoA carboxylase were elevated at 61 min. Phenformin increase AMPK activity and phosphorylation in the isolated heart. The increase in AMPK activity was always preceded by and correlated with increased cytosolic [AMP]. [1][2]

References on Phenformin hydrochloride:

[1] Danowski TS et al. Can Fam Physician. 1968 Feb;14(2):45-7.

[2] http://en.wikipedia.org/wiki/Phenformin

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.

PIK-293 is a PI3-K inhibitor. PIK-293 inhibit the p110α, p110β, p110δ, and p110γ with IC50 of 100uM,25μM,0.24μM,and 10μM.PIK-293 is the parent compand of PIK-294.

References on PIK-293:

[1] Knight, Z. A., B. Gonzalez, et al. (2006).Cell 125(4): 733-747.

PIK-294is a highly selective p110 inhibitor with an IC50 of 3 nM. PI3K contains a m-phenol and a pyrazolopyrimidine core. When PIK-294 is compared to tyrosine kinase–selective pyrazolopyrimidines such as PP20, the two molecules span more than 108 fold in relative target selectivity. PIK-294 is 20- to 60-fold more potent than the parent compound, PIK-293, making PIK-294 one of the most potent p110δ- selective inhibitors that has been reported. PIK-294 also inhibits p110α, p110β, p110γ, DNA-PK and mTOR with IC50 of 9.6, 0.67, 0.2, 48 and >50 µM. [1][2]

References on PIK-294:

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

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

PKI-402 is a selective, reversible, ATP-competitive, equipotent class I phosphatidylinositol 3-kinases (PI3K) inhibitor with IC50 of 1, 7, 16 and 14 nM for PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ, respectively. [1] PKI-402 gave rise to in vitro growth inhibition of human tumor cell lines derived from breast, brain (glioma), pancreas, and non small cell lung cancer (NSCLC) tissues. In many cases IC50 values were <100 nM. In vitro, PKI-402 suppressed phosphorylation of PI3K and mTOR effect or proteins, particularly p-Akt at threonine308 (T308), at concentrations that closely matched those that inhibited tumor cell growth. In MDA361, a breast tumor line with elevated levels of Her2 receptor, and mutant PI3K- (E545K), 30 nM PKI-402 triggered cleaved PARP, a marker for apoptosis. In vivo, PKI-402 revealed anti-tumor activity when administered by IV route in glioma (U87MG, PTEN), NSCLC (A549; K-Ras, STK11), and breast (MDA361: Her2+, PIK3CA [E545K]) xenograft models. At 25, 50, and 100 mg/kg PKI-402 caused regression of MDA361 tumors. PKI-402 effect was most pronounced at 100 mg/kg (daily for 5 days, 1 round),which decreased an initial tumor volume of 260 mm3 to 129 mm3, and inhibited tumor re-growth for 70 days. Tumor re-growth occurred between days 16-20 when PKI-402 was administered at 25and 50 mg/kg (dx5, 2 rounds). In MDA-MB-361 [breast: Her2(+) and PIK3CA mutant (E545K)], 30 nM PKI-402 induced cleaved poly(ADP-ribose) polymerase (PARP), a marker for apoptosis. [2][3]

References on PKI-402:

[1] Dehnhardt CM et al. J Med Chem. 2010 Jan 28;53(2):798-810.

[2] Robert G. Mallon et al. Mol Cancer Ther December 2009, 8(12)S1, B142

[3] Mallon R et al. Mol Cancer Ther. 2010 Apr;9(4):976-84.

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.

Quercetin is a PI3K and PKC inhibitor with IC50 of 3.8 μM and 15µg/ml. It strongly abrogated PI3K and Src kinases, mildly inhibited Akt1/2, and slightly affected PKC, p38 and ERK1/2. [1][2] Quercetin is a naturally-occurring polar auxin transport inhibitor with IC50 of 0.8, 16.7, 6.1, 11.36 µM for the inhibition of LDH% release, the inhibition of TNF-induced PMN-EC adhesion, TNF-induced inhibition of DNA synthesis and proliferation. It is a type of plant-based chemical, or phytochemical, known as a flavonol and a plant-derived flavonoid found in fruits, vegetables, leaves and grains. It also may be used as an ingredient in supplements, beverages or foods. In several studies, it may have anti-inflammatory and antioxidant properties, and it is being investigated for a wide range of potential health benefits. [3][4]

References on Quercetin(Sophoretin):

[1] Sidhu JS et al. Mol Pharmacol. 2001 May; 59(5):1138-46.

[2] Navarro-Núñez L et al. Fitoterapia. 2010 Mar; 81(2):75-80.

[3] Yu XB et al. Yao Xue Xue Bao. 1996; 31(3):176-81.

[4] http://en.wikipedia.org/wiki/Quercetin

PIK-93 is a PI4KIIIβinhibitor (IC50 at 19 nM).

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.

PP121 is a multitargeted dual receptor tyrosine kinases inhibitor with IC50 of 0.052, 1.4, 0.15, 1.1, 0.06, 0.01and 0.002 μM for p110α, p110β, p110δ, p110γ, DNA-PK, mTOR and PDGFR, respectively.

TG100–115 is a PI3K γ and -δ inhibitor (IC50 = 83 and 235 nM, respectively).

TGX-221 is a low-nanomolar range PI3Kβ inhibitor (IC50=10nM), shows about 1000-fold higher selectivity over PI3Kα, and is cell permeable. Order TGX-221 from supplier Selleck for research use only.

XL147 is a selective inhibitor of Class I PI3K isoforms.

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.

ZSTK474 is an inhibitor of PI3K γ(IC50 at 6 nM).