CNX1351

PI3Kα inhibitor CAS# 1276105-89-5

CNX1351

Catalog No. BCC6375----Order now to get a substantial discount!

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Quality Control of CNX1351

Number of papers citing our products

Chemical structure

CNX1351

3D structure

Chemical Properties of CNX1351

Cas No. 1276105-89-5 SDF Download SDF
PubChem ID 58441401 Appearance Powder
Formula C30H35N7O3S M.Wt 573.71
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 33.33 mg/mL (58.10 mM; Need ultrasonic)
Chemical Name 1-[4-[[2-(1H-indazol-4-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl]piperazin-1-yl]-6-methylhept-5-ene-1,4-dione
SMILES CC(=CC(=O)CCC(=O)N1CCN(CC1)CC2=CC3=C(S2)C(=NC(=N3)C4=C5C=NNC5=CC=C4)N6CCOCC6)C
Standard InChIKey DLNUPKDFXMWRFP-UHFFFAOYSA-N
Standard InChI InChI=1S/C30H35N7O3S/c1-20(2)16-21(38)6-7-27(39)36-10-8-35(9-11-36)19-22-17-26-28(41-22)30(37-12-14-40-15-13-37)33-29(32-26)23-4-3-5-25-24(23)18-31-34-25/h3-5,16-18H,6-15,19H2,1-2H3,(H,31,34)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of CNX1351

DescriptionCNX-1351 is a potent and isoform-selective targeted covalent PI3Kα inhibitor with IC50 of 6.8 nM.In Vitro:CNX-1351 is able to potently (EC50<100 nM) and specifically inhibit signaling in PI3Kα-dependent cancer cell lines, and this leads to a potent antiproliferative effect (GI50<100 nM). CNX-1351 inhibits PI3K signaling in SKOV3 cells, with potency (EC50 of 10-100 nM) similar to that of the pan-PI3K inhibitor. To investigate the functional consequence of inhibiting PI3Kα in cells, two cell lines with different PIK3CA activating mutations, SKOV3 ovarian cancer cells (H1047R) and MCF-7 breast cancer cells (E545K), are treated with CNX-1351 and growth is monitored. Both PIK3CA-driven cell lines are growth inhibited by exposure to CNX-1351 for 96 h (GI50 of 78 and 55 nM, respectively)[1].In Vivo:CNX-1351 inhibits p-AktSer473 in mouse spleens and bonds to PI3Kα in vivo. CNX-1351 is delivered into the intraperitoneal cavity of nude mice at 100 mg/kg once a day for 5 consecutive days (n=3 mice per group). Spleens are harvested from the mice at the indicated times after the last dose (1-24 h) and interrogated by immunoblot for P-AktSer473 or for PI3Kα occupancy. Inhibition of PI3K signaling is detected as a decrease in P-AktSer473 at 1 and 4 h after last dose[1].

References:
[1]. Nacht M, et al. Discovery of a potent and isoform-selective targeted covalent inhibitor of the lipid kinase PI3Kα. J Med Chem. 2013 Feb 14;56(3):712-21.

Protocol

Kinase Assay [1]
CNX-1351 is tested in a panel of 10 lipid kinases. CNX-1351s tested in a 10-concentration IC50 curve with 3-fold serial dilution starting at 1 μM. Reactions are carried out at 10 μM ATP. An HTRF assay format is used for PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ; ADP-GLO assay format is used for other kinases. The following substrates are used: for HTRF, phosphatidylinositol 4,5-bisphosphate; for SPHK1 and SPHK2, sphingosine; for other ADP-GLO enzymes, phosphatidylinositol. For general kinase selectivity, CNX-1351 is run in a kinase selectivity panel at using HotSpot technology and radioisotope-based P81 filtration. CNX-1351 is dissolved in pure DMSO to the final 1 μM test concentration. Substrates for the various kinases tested against CNX-1351 are prepared fresh daily in reaction buffer. Any required cofactors are then added to the substrate solution followed by kinase addition and preincubated for 30 min at room temperature. 33P-ATP (10 μM) is delivered into the reaction mixture to initiate the reaction, and reaction continued for 2 h at room temperature. The reaction is terminated, and any unreacted phosphate is washed away using 0.1% phosphoric acid prior to detection utilizing a proprietary technology. The study is performed in duplicate, and 10 μM staurosporine, a nonselective, ATP-competitive kinase inhibitor, is used as the positive control[1].

Cell Assay [1]
SKOV3 cells or MCF-7 cells are plated in SKOV3 proliferation assay medium (DMEM supplemented with 5-10% FBS and pen/strep) at a density of 5000 cells in 180 μL volume per well in Costar no. 3610 white 96-well clear flat-bottom plates and incubated overnight in a humidified 37°C incubator. A standard curve ranging from 10 000 to 50 000 cells is set up in a separate plate and allowed to adhere to the plate for 4-6 h, at which time the plate is developed using Cell Titer-Glo. The next morning, 3-fold compound dilutions ranging from 10 000 to 40 nM are prepared in proliferation medium containing 1% DMSO. Then 20 μL of each dilution is added to the SKOV3 or MCF-7 cells plated the previous day, resulting in a dose-response curve from 1000 to 4 nM. The cells are incubated for 96 h and then developed with Cell Titer Glo. The cell numbers at the end of the assay are determined using the standard curve generated at the start of the assay. Growth inhibition is calculated using the following formulas, and GI50 values are determined[1].

Animal Administration [1]
Mice[1] Female nu/nu (n=3/group) are administered compound (GDC-0941 or CNX-1351) delivered ip at 100 mg/kg once daily for 5 consecutive days. After delivery of the last dose, spleens from treated animals are harvested at 1, 4, and 24 h time points. Spleens are immediately frozen in liquid nitrogen. Samples are stored at -80°C until processing for homogenates. Homogenates are made by adding approximately 100 μL of spleen sample to a Precellys homogenizing tube containing 300 μL of cell extraction buffer plus Complete protease inhibitor and PhosStop phosphatase inhibitor and kept on ice. The sample is homogenized in a Precellys 24 homogenizer for 15 s followed by centrifugation at 16000g for 20 min at 4°C. The supernatant is moved to a new tube, and the protein concentration is determined by BCA Assay.

References:
[1]. Nacht M, et al. Discovery of a potent and isoform-selective targeted covalent inhibitor of the lipid kinase PI3Kα. J Med Chem. 2013 Feb 14;56(3):712-21.

CNX1351 Dilution Calculator

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CNX1351 Molarity Calculator

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Preparing Stock Solutions of CNX1351

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.743 mL 8.7152 mL 17.4304 mL 34.8608 mL 43.576 mL
5 mM 0.3486 mL 1.743 mL 3.4861 mL 6.9722 mL 8.7152 mL
10 mM 0.1743 mL 0.8715 mL 1.743 mL 3.4861 mL 4.3576 mL
50 mM 0.0349 mL 0.1743 mL 0.3486 mL 0.6972 mL 0.8715 mL
100 mM 0.0174 mL 0.0872 mL 0.1743 mL 0.3486 mL 0.4358 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on CNX1351

CNX1351 is a potent and selective inhibitor of PI3Kα with IC50 value of 6.8 nM [1] [2].

Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylating the 3’-hydroxyl group of phosphatidylinositol-4,5-bisphosphate (PIP2) to produce phosphatidylinositol-3,4,5-trisphosphate (PIP3). PI3Ks plays important roles in cell proliferation, survival, differentiation and metabolism [1] [2].

CNX1351 is a specific and covalent PI3Kα inhibitor. CNX1351 time-dependently and irreversibly inhibited PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ with IC50 values of 6.8, 166.0, 240.3 and 3020.0 nM, respectively. In SKOV3 ovarian cancer cells with a mutation in PIK3CA that resulted in a constitutively activated PI3Kα, CNX1351 inhibited PI3K signaling with EC50 values of 10-100 nM. In MCF-7 breast cancer cells (E545K) and SKOV3 ovarian cancer cells (H1047R) with different PIK3CA activating mutations, CNX1351 inhibited cell growth with GI50 values of 55 and 78 nM, respectively [1].

In nude mice, CNX1351 (100 mg/kg ip) irreversibly bonded to p110α and inhibited P-AktSer473 expression [1].

References:
[1].  Nacht M, Qiao L, Sheets MP, et al. Discovery of a potent and isoform-selective targeted covalent inhibitor of the lipid kinase PI3Kα. J Med Chem, 2013, 56(3): 712-721.
[2].  Jeong Y, Kwon D, Hong S. Selective and potent small-molecule inhibitors of PI3Ks. Future Med Chem, 2014, 6(7): 737-756.

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Description

CNX-1351 is a potent and isoform-selective targeted covalent PI3Kα inhibitor with IC50 of 6.8 nM.

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