CGP-57380
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MedKoo CAT#: 407307

CAS#: 522629-08-9

Description: CGP-57380 is a selective inhibitor of MAP kinase-interacting kinase 1 (MNK1) in vitro (IC50 = 2.2 μM). MNK1 overexpression was confirmed in both primary GBMs and glioma cell lines. Inhibition of MNK1 activity in GBM cells by the small molecule CGP57380 suppressed eIF4E phosphorylation, proliferation, and colony formation whereas concomitant treatment with CGP57380 and the mTOR inhibitor rapamycin accentuated growth inhibition and cell-cycle arrest.


Chemical Structure

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CGP-57380
CAS# 522629-08-9

Theoretical Analysis

MedKoo Cat#: 407307
Name: CGP-57380
CAS#: 522629-08-9
Chemical Formula: C11H9FN6
Exact Mass: 244.0873
Molecular Weight: 244.2334
Elemental Analysis: C, 54.10; H, 3.71; F, 7.78; N, 34.41

Price and Availability

Size Price Availability Quantity
25.0mg USD 250.0 2 Weeks
50.0mg USD 450.0 2 Weeks
100.0mg USD 750.0 2 Weeks
200.0mg USD 1250.0 2 Weeks
500.0mg USD 2250.0 2 Weeks
1.0g USD 3250.0 2 Weeks
2.0g USD 5450.0 2 Weeks
Bulk inquiry

Synonym: CGP-57380; CGP57380; CGP 57380.

IUPAC/Chemical Name: N3-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3,4-diamine

InChi Key: UQPMANVRZYYQMD-UHFFFAOYSA-N

InChi Code: InChI=1S/C11H9FN6/c12-6-1-3-7(4-2-6)16-11-8-9(13)14-5-15-10(8)17-18-11/h1-5H,(H4,13,14,15,16,17,18)

SMILES Code: NC1=C2C(NN=C2NC3=CC=C(F)C=C3)=NC=N1

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Product Data:

Biological target: 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.
In vitro activity: It was found that MNK inhibition with CGP57380 decreased eIF4E phosphorylation and prevented the eIF4E mediated increase in nuclear β-catenin in K562-eIF4EWT but not K562-eIF4ES209D cells (Fig. 4 A and B). In reporter assays, CGP57380 abolished β-catenin activity in K562-eIF4EWT but not K562-eIF4ES209D cells, whereas cercosporin (a positive control for Wnt inhibition that acts directly to disrupt TCF/β-catenin complexes) eliminated activity in both cell lines (Fig. 4C). CGP57380 treatment also reduced transcript levels of several Wnt target genes (LEF1, AXIN2, and CYCLIND1) in K562-eIF4EWT but not K562-eIF4ES209D (Fig. 4D). The ability of CGP57380 to inhibit eIF4E phosphorylation and β-catenin signaling in primary BC GMPs was assessed. The primary CD34+ BC cells were sorted to obtain the HSC and GMP fractions and were treated with CGP57380 or imatinib (IM). It was found that CGP57380 effectively inhibited eIF4E phosphorylation as well as β-catenin activation, whereas IM was unable to prevent either despite inhibition of BCR-ABL1 (as readout by CrkL phosphorylation; Fig. 4 J and K). Reference: Proc Natl Acad Sci U S A. 2013 Jun 18;110(25):E2298-307. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23737503/
In vivo activity: Findings suggested that MNK inhibition might effectively control BC CML because it extinguishes BC LSC function in vitro. To test this possibility in an in vivo BC model, the effect of CGP57380 on the ability of BC GMPs to serially transplant immunodeficient nonobese diabetic/SCID IL2Rγ-deficient mice [NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice] was investigated. In preliminary studies, it was found that a brief 48-h in vitro exposure to CGP57380 was able to delay the engraftment of BC LSCs in NSG mice, as well as reduce the leukemia cell burden in engrafted animals (Fig. S7 A and B), while leaving the normal CD34+ cell engraftment untouched (Fig. S7 C and D). These results encouraged a determination if the self-renewing capacity of BC LSCs could be targeted in vivo by small-molecule MNK inhibitors. Here, we FACS-sorted GMPs from a BC sample as previously described (6), and injected them intrafemorally into 8- to 12-wk-old female NSG mice (Fig. S8A). At 6 wk posttransplantation, engrafted mice were treated for 3 wk with DMSO, CGP57380, or dasatinib (n = 5 mice per treatment group). At the end of the treatment period, all the mice were killed, and human cells were obtained from hematopoietic tissues by using immunomagnetic beads. No difference in the percentage of CD45+ human cells in the peripheral blood or BM of each of the treatment groups was found (Fig. 6A). However, it was observed that dasatinib and CGP57380 had specific activity against committed BC progenitors, as they significantly reduced the number of colony forming units detected in BM (P ≤ 0.05 and P ≤ 0.005, respectively) compared with control, although the effect of CGP57380 was greater (Fig. 6B). Reference: Proc Natl Acad Sci U S A. 2013 Jun 18;110(25):E2298-307. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23737503/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 6.0 24.57

Preparing Stock Solutions

The following data is based on the product molecular weight 244.2334 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
In vitro protocol: 1. Lim S, Saw TY, Zhang M, Janes MR, Nacro K, Hill J, Lim AQ, Chang CT, Fruman DA, Rizzieri DA, Tan SY, Fan H, Chuah CT, Ong ST. 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. doi: 10.1073/pnas.1301838110. Epub 2013 Jun 4. PMID: 23737503; PMCID: PMC3690864. 2. Chrestensen CA, Eschenroeder A, Ross WG, Ueda T, Watanabe-Fukunaga R, Fukunaga R, Sturgill TW. Loss of MNK function sensitizes fibroblasts to serum-withdrawal induced apoptosis. Genes Cells. 2007 Oct;12(10):1133-40. doi: 10.1111/j.1365-2443.2007.01122.x. PMID: 17903173.
In vivo protocol: 1. Lim S, Saw TY, Zhang M, Janes MR, Nacro K, Hill J, Lim AQ, Chang CT, Fruman DA, Rizzieri DA, Tan SY, Fan H, Chuah CT, Ong ST. 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. doi: 10.1073/pnas.1301838110. Epub 2013 Jun 4. PMID: 23737503; PMCID: PMC3690864.

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1: Martínez A, Sesé M, Losa JH, Robichaud N, Sonenberg N, Aasen T, Ramón Y Cajal S. Phosphorylation of eIF4E Confers Resistance to Cellular Stress and DNA-Damaging Agents through an Interaction with 4E-T: A Rationale for Novel Therapeutic Approaches. PLoS One. 2015 Apr 29;10(4):e0123352. doi: 10.1371/journal.pone.0123352. eCollection 2015. PubMed PMID: 25923732; PubMed Central PMCID: PMC4414544.

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6: Lim S, Saw TY, Zhang M, Janes MR, Nacro K, Hill J, Lim AQ, Chang CT, Fruman DA, Rizzieri DA, Tan SY, Fan H, Chuah CT, Ong ST. 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. doi: 10.1073/pnas.1301838110. Epub 2013 Jun 4. PubMed PMID: 23737503; PubMed Central PMCID: PMC3690864.

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8: Gorentla BK, Krishna S, Shin J, Inoue M, Shinohara ML, Grayson JM, Fukunaga R, Zhong XP. Mnk1 and 2 are dispensable for T cell development and activation but important for the pathogenesis of experimental autoimmune encephalomyelitis. J Immunol. 2013 Feb 1;190(3):1026-37. doi: 10.4049/jimmunol.1200026. Epub 2012 Dec 26. PubMed PMID: 23269249; PubMed Central PMCID: PMC3552100.

9: Shi Y, Frost P, Hoang B, Yang Y, Fukunaga R, Gera J, Lichtenstein A. MNK kinases facilitate c-myc IRES activity in rapamycin-treated multiple myeloma cells. Oncogene. 2013 Jan 10;32(2):190-7. doi: 10.1038/onc.2012.43. Epub 2012 Feb 27. PubMed PMID: 22370634; PubMed Central PMCID: PMC3401333.

10: Ziaei S, Shimada N, Kucharavy H, Hubbard K. MNK1 expression increases during cellular senescence and modulates the subcellular localization of hnRNP A1. Exp Cell Res. 2012 Mar 10;318(5):500-8. doi: 10.1016/j.yexcr.2011.12.015. Epub 2011 Dec 27. PubMed PMID: 22227431; PubMed Central PMCID: PMC3288735.

11: Grzmil M, Morin P Jr, Lino MM, Merlo A, Frank S, Wang Y, Moncayo G, Hemmings BA. MAP kinase-interacting kinase 1 regulates SMAD2-dependent TGF-β signaling pathway in human glioblastoma. Cancer Res. 2011 Mar 15;71(6):2392-402. doi: 10.1158/0008-5472.CAN-10-3112. Epub 2011 Mar 14. PubMed PMID: 21406405.

12: Korneeva NL, Soung YH, Kim HI, Giordano A, Rhoads RE, Gram H, Chung J. Mnk mediates integrin α6β4-dependent eIF4E phosphorylation and translation of VEGF mRNA. Mol Cancer Res. 2010 Dec;8(12):1571-8. doi: 10.1158/1541-7786.MCR-10-0091. Epub 2010 Oct 21. PubMed PMID: 21047768.

13: Wheater MJ, Johnson PW, Blaydes JP. The role of MNK proteins and eIF4E phosphorylation in breast cancer cell proliferation and survival. Cancer Biol Ther. 2010 Oct 1;10(7):728-35. doi: 10.4161/cbt.10.7.12965. Epub 2010 Oct 1. PubMed PMID: 20686366; PubMed Central PMCID: PMC3093812.

14: Zhang M, Fu W, Prabhu S, Moore JC, Ko J, Kim JW, Druker BJ, Trapp V, Fruehauf J, Gram H, Fan HY, Ong ST. Inhibition of polysome assembly enhances imatinib activity against chronic myelogenous leukemia and overcomes imatinib resistance. Mol Cell Biol. 2008 Oct;28(20):6496-509. doi: 10.1128/MCB.00477-08. Epub 2008 Aug 11. PubMed PMID: 18694961; PubMed Central PMCID: PMC2577410.

15: Kjellerup RB, Kragballe K, Iversen L, Johansen C. Pro-inflammatory cytokine release in keratinocytes is mediated through the MAPK signal-integrating kinases. Exp Dermatol. 2008 Jun;17(6):498-504. Epub 2007 Dec 13. PubMed PMID: 18081851.

16: Rowlett RM, Chrestensen CA, Nyce M, Harp MG, Pelo JW, Cominelli F, Ernst PB, Pizarro TT, Sturgill TW, Worthington MT. MNK kinases regulate multiple TLR pathways and innate proinflammatory cytokines in macrophages. Am J Physiol Gastrointest Liver Physiol. 2008 Feb;294(2):G452-9. Epub 2007 Nov 21. PubMed PMID: 18032482.

17: Chrestensen CA, Eschenroeder A, Ross WG, Ueda T, Watanabe-Fukunaga R, Fukunaga R, Sturgill TW. Loss of MNK function sensitizes fibroblasts to serum-withdrawal induced apoptosis. Genes Cells. 2007 Oct;12(10):1133-40. PubMed PMID: 17903173.

18: Schümann M, Dobbelstein M. Adenovirus-induced extracellular signal-regulated kinase phosphorylation during the late phase of infection enhances viral protein levels and virus progeny. Cancer Res. 2006 Feb 1;66(3):1282-8. PubMed PMID: 16452180.

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20: Cherla RP, Lee SY, Mees PL, Tesh VL. Shiga toxin 1-induced cytokine production is mediated by MAP kinase pathways and translation initiation factor eIF4E in the macrophage-like THP-1 cell line. J Leukoc Biol. 2006 Feb;79(2):397-407. Epub 2005 Nov 21. PubMed PMID: 16301326.