CGP 57380

Names

[ Name ]:
CGP 57380

[Synonym ]:
1H-Pyrazolo[3,4-d]pyrimidine-3,4-diamine, N-(4-fluorophenyl)-
N-(4-Fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3,4-diamine
CGP57380 N3-(4-fluorophenyl)-1h-pyrazolo[3,4-d]pyrimidine-3,4-diamine
CGP-57380
CGP 57380

Biological Activity

[Description]:

CGP 57380 is a cell-permeable pyrazolo-pyrimidine compound that acts as a selective inhibitor of Mnk1 with IC50 of 2.2 μM, but has no inhibitory activity against p38, JNK1, ERK1/2, PKC, or Src-like kinases.

[Related Catalog]:

Signaling Pathways >> MAPK/ERK Pathway >> MNK

Research Areas >> Cancer

[Target]

MNK1:2.2 μM (IC50)

[In Vitro]

CGP57380 inhibits phosphorylation of eIF4E in cellular assays with IC50 of about 3 μM. CGP57380 causes dephosphorylation of eIF4E, and induces a further increase in the cap-dependent reporter in 293 cells[1]. CGP57380 results in dose-dependent decreases in Ang II-stimulated phosphorylation of eIF4E, protein synthesis, and VSMC hypertrophy[2]. CGP57380 sensitizes wild-type cells for serum-withdrawal induced apoptosis in mouse embryo fibroblasts (MEFs)[3]. CGP57380 prevents the serial replating function of BC progenitors[4].

[In Vivo]

CGP57380 (40 mg/kg/d i.p.) potently extinguishes the ability of BC CML cells to serially transplant-immunodeficient mice and function as LSCs[4].

[Kinase Assay]

Recombinant p38 isoforms are activated by Mkk6(E) under the following conditions: p38 (100 ng/mL), Mkk6(E) (30 ng/mL), ATP (100 mM) are mixed in kinase buffer (25 mM Hepes, 25 mM b-glycerophosphate, 0.1 mM sodium orthovanadate, 25 mM MgCl2, 2.5 mM DTT, pH 7.4) and incubated for 30 min at 30°C. A typical assay reaction for Mnk1 activity contained Mnk1 (2 ng/mL), HA-eIF4E (10 ng/mL), ATP (300 mM) in kinase buffer. The reaction is started by addition of activated p38 (0.03-3 ng/mL) and stopped after 30 min at 30°C by addition of SDS loading buffer. Inhibitors of Mnk1 are identified under the same assay conditions, except that Mnk1 is pre-activated using active p38a before exposure to the substrate and inhibitors.

[Animal admin]

CD34+ cells (5×105) or GMPs (1×105) are resuspended in 25 μL 1% FBS/PBS solution and injected into the right femur of 8- to 10-wk-old sublethally irradiated (200 cGy) female mice (n=5 mice per group). Mice injected with 1% FBS/PBS solution serve as a sham control for each experiment. Beginning at 4 wk posttransplantation, mice are monitored for engraftment of human cells by flow cytometry. At 6 wk after transplantation, engrafted mice are treated with vehicle alone, dasatinib (5 mg/kg/d) by gavage, or CGP57380 (40 mg/kg/d) intraperitoneally for 3 wk (n=5 mice per group). At the end of treatment, mice are euthanized, and CD45+ cells are isolated from BM and spleen by using anti-human CD45-specific immunomagnetic microbeads. An aliquot of 1×105 human CD45+ cells is seeded into methylcellulose for the colony forming cell (CFC) assay, and colonies are enumerated after 2 wk. All of the remaining human cells from each primary transplant recipient are then transplanted by intrafemoral injection into secondary recipients, and human engraftment is monitored at 2-wk intervals beginning at 4 wk. At the end of 16 wk, all mice are euthanized. Engraftment in BM and blood is assessed by flow cytometry, and BCR-ABL1 transcripts are detected by RT-PCR.

[References]

[1]. Knauf U, et al. Negative regulation of protein translation by mitogen-activated protein kinase-interacting kinases 1 and 2. Mol Cell Biol. 2001 Aug;21(16):5500-11.

[2]. Ishida M, et al. Mnk1 is required for angiotensin II-induced protein synthesis in vascular smooth muscle cells. Circ Res. 2003 Dec 12;93(12):1218-24. Epub 2003 Nov 6

[3]. Chrestensen CA, et al. Loss of MNK function sensitizes fibroblasts to serum-withdrawal induced apoptosis. Genes Cells. 2007 Oct;12(10):1133-40.

[4]. Lim S, et al. Targeting of the MNK-eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function. Proc Natl Acad Sci U S A. 2013 Jun 18;110(25):E2298-307

[Related Small Molecules]

eFT508 | Cercosporamide | ETC-206 | SEL-201

Chemical & Physical Properties

[ Density]:
1.6±0.1 g/cm3

[ Boiling Point ]:
541.6±50.0 °C at 760 mmHg

[ Molecular Formula ]:
C₁₁H₉FN₆

[ Molecular Weight ]:
244.228

[ Flash Point ]:
281.4±30.1 °C

[ Exact Mass ]:
244.087280

[ PSA ]:
92.51000

[ LogP ]:
1.28

[ Vapour Pressure ]:
0.0±1.4 mmHg at 25°C

[ Index of Refraction ]:
1.809

[ Storage condition ]:
-20℃

MSDS

Click to get detail MSDS

Safety Information

[ Symbol ]:

GHS07

[ Signal Word ]:
Warning

[ Hazard Statements ]:
H319

[ Precautionary Statements ]:
P305 + P351 + P338

[ Personal Protective Equipment ]:
Eyeshields;Gloves;type N95 (US);type P1 (EN143) respirator filter

[ RIDADR ]:
NONH for all modes of transport

Articles

Targeting RNA transcription and translation in ovarian cancer cells with pharmacological inhibitor CDKI-73.

Oncotarget 5(17) , 7691-704, (2014)

Dysregulation of cellular transcription and translation is a fundamental hallmark of cancer. As CDK9 and Mnks play pivotal roles in the regulation of RNA transcription and protein synthesis, respectiv...

MNKs act as a regulatory switch for eIF4E1 and eIF4E3 driven mRNA translation in DLBCL.

Nat. Commun. 5 , 5413, (2014)

The phosphorylation of eIF4E1 at serine 209 by MNK1 or MNK2 has been shown to initiate oncogenic mRNA translation, a process that favours cancer development and maintenance. Here, we interrogate the M...

Pharmacologic co-inhibition of Mnks and mTORC1 synergistically suppresses proliferation and perturbs cell cycle progression in blast crisis-chronic myeloid leukemia cells.

Cancer Lett. 357(2) , 612-23, (2015)

The Ras/Raf/MAPK and PI3K/Akt/mTORC1 cascades are two most aberrantly regulated pathways in cancers. As MAPK-interacting kinases (Mnks) are part of the convergent node of these two pathways, and play ...