1. PI3K/Akt/mTOR
  2. PI3K
  3. CNX-1351

CNX-1351 

Cat. No.: HY-16596 Purity: 99.88%
Handling Instructions

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

For research use only. We do not sell to patients.

CNX-1351 Chemical Structure

CNX-1351 Chemical Structure

CAS No. : 1276105-89-5

Size Price Stock Quantity
10 mM * 1 mL in DMSO USD 164 In-stock
Estimated Time of Arrival: December 31
5 mg USD 130 In-stock
Estimated Time of Arrival: December 31
10 mg USD 240 In-stock
Estimated Time of Arrival: December 31
50 mg USD 792 In-stock
Estimated Time of Arrival: December 31
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Description

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

IC50 & Target[1]

PI3Kα

6.8 nM (IC50)

PI3Kβ

166 nM (IC50)

PI3Kδ

240.3 nM (IC50)

PI3Kγ

3020 nM (IC50)

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].

Molecular Weight

573.71

Formula

C₃₀H₃₅N₇O₃S

CAS No.

1276105-89-5

SMILES

C/C(C)=C/C(CCC(N1CCN(CC2=CC3=NC(C4=CC=CC5=C4C=NN5)=NC(N6CCOCC6)=C3S2)CC1)=O)=O

Shipping

Room temperature in continental US; may vary elsewhere.

Storage
Powder -20°C 3 years
  4°C 2 years
In solvent -80°C 6 months
  -20°C 1 month
Solvent & Solubility
In Vitro: 

DMSO : ≥ 21.8 mg/mL (38.00 mM)

*"≥" means soluble, but saturation unknown.

Preparing
Stock Solutions
Concentration Solvent Mass 1 mg 5 mg 10 mg
1 mM 1.7430 mL 8.7152 mL 17.4304 mL
5 mM 0.3486 mL 1.7430 mL 3.4861 mL
10 mM 0.1743 mL 0.8715 mL 1.7430 mL
*Please refer to the solubility information to select the appropriate solvent.
References
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].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

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].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

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.

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

References

Purity: 99.88%

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Keywords:

CNX-1351CNX1351CNX 1351PI3KPhosphoinositide 3-kinaseInhibitorinhibitorinhibit

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CNX-1351
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