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A 419259 trihydrochloride

LCK inhibitor, orally available CAS# 1435934-25-0

A 419259 trihydrochloride

Catalog No. BCC4308----Order now to get a substantial discount!

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Chemical structure

A 419259 trihydrochloride

3D structure

Chemical Properties of A 419259 trihydrochloride

Cas No. 1435934-25-0 SDF Download SDF
PubChem ID 76848881 Appearance Powder
Formula C29H37Cl3N6O M.Wt 592
Type of Compound N/A Storage Desiccate at -20°C
Synonyms RK 20449 trihydrochloride
Solubility H2O : ≥ 55 mg/mL (92.91 mM)
DMSO : 1 mg/mL (1.69 mM; Need ultrasonic)
*"≥" means soluble, but saturation unknown.
Chemical Name 7-[4-(4-methylpiperazin-1-yl)cyclohexyl]-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-amine;trihydrochloride
SMILES CN1CCN(CC1)C2CCC(CC2)N3C=C(C4=C3N=CN=C4N)C5=CC=C(C=C5)OC6=CC=CC=C6.Cl.Cl.Cl
Standard InChIKey ALRMEQIQFCUAMR-UHFFFAOYSA-N
Standard InChI InChI=1S/C29H34N6O.3ClH/c1-33-15-17-34(18-16-33)22-9-11-23(12-10-22)35-19-26(27-28(30)31-20-32-29(27)35)21-7-13-25(14-8-21)36-24-5-3-2-4-6-24;;;/h2-8,13-14,19-20,22-23H,9-12,15-18H2,1H3,(H2,30,31,32);3*1H
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 A 419259 trihydrochloride

DescriptionPotent Hck inhibitor (IC50 = 0.43 nM). Also inhibits other Src family kinases (SFKs). Suppresses proliferation and induces apoptosis in CML cell lines including CD34+. Also inhibits acute myeloid leukemia (AML) stem cell proliferation in vitro and in vivo.

A 419259 trihydrochloride Dilution Calculator

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A 419259 trihydrochloride Molarity Calculator

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Preparing Stock Solutions of A 419259 trihydrochloride

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.6892 mL 8.4459 mL 16.8919 mL 33.7838 mL 42.2297 mL
5 mM 0.3378 mL 1.6892 mL 3.3784 mL 6.7568 mL 8.4459 mL
10 mM 0.1689 mL 0.8446 mL 1.6892 mL 3.3784 mL 4.223 mL
50 mM 0.0338 mL 0.1689 mL 0.3378 mL 0.6757 mL 0.8446 mL
100 mM 0.0169 mL 0.0845 mL 0.1689 mL 0.3378 mL 0.4223 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 A 419259 trihydrochloride

A 419259 trihydrochloride is an orally available inhibitor of lck with IC50 value of 15 nM [1].

Lck is a src family tyrosine kinase. Inhibition of this enzyme results in a prevention of T-cell activation and provides an application for treating T-cell dependent processes such as autoimmune and inflammatory diseases. A 419259 trihydrochloride is screened out by its potent inhibitory activity against the recombinant lck (64–509) with IC50 value of 15nM. It is also a selective inhibitor. It shows inactive against a panel of other kinases including cMet, IGFR, PKC and PDGFR. Besides that, A 419259 trihydrochloride is found to inhibit the production of IL-2 with IC50 value of 25nM in Jurkat cells. Moreover, administration of A 419259 trihydrochloride reduces IL-2 production in mice with ED50 value of 2.5 mg/kg. A 419259 trihydrochloride also has efficacy of the antigen specific T-Cell immune response. Administration of this compound inhibits IFN-γ production during the in vivo priming phase [1].

Reference:
[1] Calderwood D J, Johnston D N, Munschauer R, et al.  Pyrrolo [2, 3-d] pyrimidines containing diverse N-7 substituents as potent inhibitors of Lck. Bioorganic & medicinal chemistry letters, 2002, 12(12): 1683-1686.

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References on A 419259 trihydrochloride

A pyrrolo-pyrimidine derivative targets human primary AML stem cells in vivo.[Pubmed:23596204]

Sci Transl Med. 2013 Apr 17;5(181):181ra52.

Leukemia stem cells (LSCs) that survive conventional chemotherapy are thought to contribute to disease relapse, leading to poor long-term outcomes for patients with acute myeloid leukemia (AML). We previously identified a Src-family kinase (SFK) member, hematopoietic cell kinase (HCK), as a molecular target that is highly differentially expressed in human primary LSCs compared with human normal hematopoietic stem cells (HSCs). We performed a large-scale chemical library screen that integrated a high-throughput enzyme inhibition assay, in silico binding prediction, and crystal structure determination and found a candidate HCK inhibitor, RK-20449, a pyrrolo-pyrimidine derivative with an enzymatic IC50 (half maximal inhibitory concentration) in the subnanomolar range. A crystal structure revealed that RK-20449 bound the activation pocket of HCK. In vivo administration of RK-20449 to nonobese diabetic (NOD)/severe combined immunodeficient (SCID)/IL2rg(null) mice engrafted with highly aggressive therapy-resistant AML significantly reduced human LSC and non-stem AML burden. By eliminating chemotherapy-resistant LSCs, RK-20449 may help to prevent relapse and lead to improved patient outcomes in AML.

An inhibitor-resistant mutant of Hck protects CML cells against the antiproliferative and apoptotic effects of the broad-spectrum Src family kinase inhibitor A-419259.[Pubmed:18794796]

Oncogene. 2008 Nov 27;27(56):7055-69.

Chronic myelogenous leukemia (CML) is driven by Bcr-Abl, a constitutively active protein-tyrosine kinase that stimulates proliferation and survival of myeloid progenitors. Global inhibition of myeloid Src family kinase (SFK) activity with the broad-spectrum pyrrolo-pyrimidine inhibitor, A-419259, blocks proliferation and induces apoptosis in CML cell lines, suggesting that transformation by Bcr-Abl requires SFK activity. However, the contribution of Hck and other individual SFKs to Bcr-Abl signaling is less clear. Here, we developed an A-419259-resistant mutant of Hck by replacing the gatekeeper residue (Thr-338; c-Src numbering) in the inhibitor-binding site with a bulkier methionine residue (Hck-T338M). This substitution reduced Hck sensitivity to A-419259 by more than 30-fold without significantly affecting kinase activity in vitro. Expression of Hck-T338M protected K-562 CML cells and Bcr-Abl-transformed TF-1 myeloid cells from the apoptotic and antiproliferative effects of A-419259. These effects correlated with persistence of Hck-T338M kinase activity in the presence of the compound, and were accompanied by sustained Erk and Stat5 activation. In contrast, control cells expressing equivalent levels of wild-type Hck retained sensitivity to the inhibitor. We also show for the first time that A-419259 induces cell-cycle arrest and apoptosis in primary CD34(+) CML cells with equal potency to imatinib. These data suggest that Hck has a nonredundant function as a key downstream signaling partner for Bcr-Abl and may represent a potential drug target in CML.

Selective pyrrolo-pyrimidine inhibitors reveal a necessary role for Src family kinases in Bcr-Abl signal transduction and oncogenesis.[Pubmed:12444544]

Oncogene. 2002 Nov 21;21(53):8075-88.

Chronic myelogenous leukemia (CML) is defined by the presence of the Philadelphia (Ph) chromosome, which results in the expression of the 210 kDa Bcr-Abl tyrosine kinase. Bcr-Abl constitutively activates several signaling proteins important for the proliferation and survival of myeloid progenitors, including the Src family kinases Hck and Lyn, the Stat5 transcription factor and upstream components of the Ras/Erk pathway. Recently, we found that kinase-defective Hck blocks Bcr-Abl-induced transformation of DAGM myeloid leukemia cells to cytokine independence, suggesting that activation of the Src kinase family may be essential to oncogenic signaling by Bcr-Abl. To investigate the contribution of Src kinases to Bcr-Abl signaling in vivo, we used the pyrrolo-pyrimidine Src kinase inhibitors PP2 and A-419259. Treatment of the Ph+ CML cell lines K-562 and Meg-01 with either compound resulted in growth arrest and induction of apoptosis, while the Ph- leukemia cell lines TF-1 and HEL were unaffected over the same concentration ranges. Suppression of Ph+ cell growth by PP2 and A-419259 correlated with a decrease in Src kinase autophosphorylation. Both inhibitors blocked Stat5 and Erk activation, consistent with the suppressive effects of the compounds on survival and proliferation. In contrast, the phosphotyrosine content of Bcr-Abl and its endogenous substrate CrkL was unchanged at inhibitor concentrations that induced apoptosis, blocked oncogenic signaling and inhibited Src kinases. These data implicate the Src kinase family in Stat5 and Erk activation downstream of Bcr-Abl, and identify myeloid-specific Src kinases as potential drug targets in CML.

Description

A 419259 trihydrochloride is a Src family kinases inhibitor with IC50s of 9 nM, 3 nM and 3 nM for Src, Lck and Lyn, respectively.

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