AMG319PI3Kδ inhibitor CAS# 1608125-21-8 |
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Quality Control & MSDS
Number of papers citing our products
Chemical structure
3D structure
Cas No. | 1608125-21-8 | SDF | Download SDF |
PubChem ID | 68947304 | Appearance | Powder |
Formula | C21H16FN7 | M.Wt | 385.4 |
Type of Compound | N/A | Storage | Desiccate at -20°C |
Solubility | DMSO : 50 mg/mL (129.74 mM; Need ultrasonic) | ||
Chemical Name | N-[(1S)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7H-purin-6-amine | ||
SMILES | CC(C1=C(N=C2C=C(C=CC2=C1)F)C3=CC=CC=N3)NC4=NC=NC5=C4NC=N5 | ||
Standard InChIKey | KWRYMZHCQIOOEB-LBPRGKRZSA-N | ||
Standard InChI | InChI=1S/C21H16FN7/c1-12(28-21-19-20(25-10-24-19)26-11-27-21)15-8-13-5-6-14(22)9-17(13)29-18(15)16-4-2-3-7-23-16/h2-12H,1H3,(H2,24,25,26,27,28)/t12-/m0/s1 | ||
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. |
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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. |
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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. |
Description | AMG319 is a potent and selective PI3Kδ kinase inhibitor with IC50 of 18 nM.In Vitro:AMG319 inhibits PI3Kδ, PI3Kγ, PI3Kβ and PI3Kα with IC50s of 18 nM, 850 nM, 2.7 μM and 33 μM, respectively. AMG319, a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation. AMG319 has minimal CYP3A4/2D6 inhibition and does not inhibit CYPs (1A2, 2C8, 2C9, 2C19, 2E1, all >20 μM). There is no time dependent inhibition (TDI) against CYPs 3A4, 2D6, 1A2, and 2C9 nor CYP induction (3A4, 2D6, 1A2, 2B6) as measured in hepatocytes. AMG319 is clean in a hERG binding assay (>25 μM), and an Ames micronucleus test proved negative. AMG319 has minimal effects in a BSEP assay up to >200 μM. Additionally, AMG319 is clean in a large side effect profiling panel (CEREP) and has no activity in a large panel of 359 unique protein kinases tested at 10 μM drug concentration[1].In Vivo:The study is performed to determine the correlation between biochemical coverage (i.e., pAKT) with functional activity in vivo. AMG319 achieves this coverage at the 3 mg/kg level, which also coveres the human whole blood assay (HWB) (CD-69) IC90 at trough for a full 24 h period. The lower doses 0.1, 0.3, and 1 mg/kg cover trough concentrations between the HWB IC50 and IC90 and evince partial efficacy. Similarly, the plasma concentration of AMG319 covers the IC90 at the 1 mg/kg dose of the mouse anti-IgM pAKT in vitro assay[1]. References: |
AMG319 Dilution Calculator
AMG319 Molarity Calculator
1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
1 mM | 2.5947 mL | 12.9735 mL | 25.9471 mL | 51.8941 mL | 64.8677 mL |
5 mM | 0.5189 mL | 2.5947 mL | 5.1894 mL | 10.3788 mL | 12.9735 mL |
10 mM | 0.2595 mL | 1.2974 mL | 2.5947 mL | 5.1894 mL | 6.4868 mL |
50 mM | 0.0519 mL | 0.2595 mL | 0.5189 mL | 1.0379 mL | 1.2974 mL |
100 mM | 0.0259 mL | 0.1297 mL | 0.2595 mL | 0.5189 mL | 0.6487 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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AMG 319, a highly selective inhibitor of phosphoinositide 3-kinase p110δ isoform (PI3Kδ) [1], with an IC50 value less than 10 nM [2].
PI3Kδ plays an essential role in B-cell receptor (BCR) signaling. PI3Kδ is expressed in lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) [1].
C-Akt, a serine-threonine kinase is one target of PI39K. C-Akt is the prototypical member of a mammalian Akt isoform family. The regulation to Akt may be phosphorylation or direct binding the Akt pleckstrin homology domain with PI39K lipid products. PI39K-independent Akt stimuli had been identified [3]. AMG 319 inhibited basal AKT phosphorylation and proliferation in lymphoid tumor cells [1].
28 patients received AMG 319. In a CLL patient after 1 dose of AMG 319, grade 3 hemolytic anemia at 25 mg was produced. All CLL samples with an inducible signal (60%) showed coverage of BCR-induced pAKT (ex-vivo IgD stimulated) dose-dependently; at 400 mg, near complete inhibition was seen for 24 hours. Baseline % of T-regulatory cells was elevated in CLL patients (14.4% ± 7.6%). But during treatment (14/19 patients), the elevated T regulatory cells tended to normalize. This suggested that the drug might produce immune restoration. By physical exam, all 20 evaluable patients showed greater than 50% lymph node (LN) reduction, 15 (75%) patients showed greater than 90% LN reduction. This response was present in all cytogenetic subtypes [1].
References:
[1]. Glenn M, Mato AR, Allgood SD, et al. First-in-human study of AMG 319, a highly selective, small molecule inhibitor of PI3Kδ, in adult patients with relapsed or refractory lymphoid malignancies. Blood, 2013, 122(21): 678-678.
[2]. Brana I, Siu LL. Clinical development of phosphatidylinositol 3-kinase inhibitors for cancer treatment. BMC medicine, 2012, 10(1): 1.
[3]. Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell, 1997, 91(2): 231-241.
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Discovery and in vivo evaluation of (S)-N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and related PI3Kdelta inhibitors for inflammation and autoimmune disease.[Pubmed:25469863]
J Med Chem. 2015 Jan 8;58(1):480-511.
The development and optimization of a series of quinolinylpurines as potent and selective PI3Kdelta kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.