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    BI-D1870
    BI-D1870

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0238
    CAS #: 501437-28-1Purity ≥98%

    Description: BI-D1870 is a specific, cell permeable and ATP-competitive inhibitor of RSK1/2/3/4 (p90 ribosomal S6 kinase) with the potential to treat autoimmune encephalomyelitis (EAE). It inhibits RSK1/2/3/4 with IC50s of 31 nM/24 nM/18 nM/15 nM in cell-free assays, respectively. and displays 10- to 100-fold higher selectivity for RSK over MST2, GSK-3β, MARK3, CK1 and Aurora B. RSKs are serine/threonine kinases that are involved in various cellular processes including growth, survival, and motility. BI-D1870 also showed potent antiproliferative activity in vitro. 

    References: Biochem J. 2007 Jan 1; 401(Pt 1): 29–38.  

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    Molecular Weight (MW)

    391.42

    Formula

    C19H23F2N5O2

    CAS No.

    501437-28-1

    Storage

    -20℃ for 3 years in powder form

    -80℃ for 2 years in solvent

    Solubility (In vitro)

    DMSO: 78 mg/mL (199.3 mM)

    Water: <1 mg/mL

    Ethanol:  <1 mg/mL

    Solubility (In vivo)

    30% PEG400+0.5% Tween80+5% propylene glycol: 30mg/mL

    Synonyms

    BI D1870; BID1870; BI-D1870

    Chemical Name: 2-((3,5-difluoro-4-hydroxyphenyl)amino)-8-isopentyl-5,7-dimethyl-7,8-dihydropteridin-6(5H)-one.

    InChi Key: DTEKTGDVSARYDS-UHFFFAOYSA-N

    InChi Code: InChI=1S/C19H23F2N5O2/c1-10(2)5-6-26-11(3)18(28)25(4)15-9-22-19(24-17(15)26)23-12-7-13(20)16(27)14(21)8-12/h7-11,27H,5-6H2,1-4H3,(H,22,23,24)

    SMILES Code: O=C1N(C)C2=CN=C(NC3=CC(F)=C(O)C(F)=C3)N=C2N(CCC(C)C)C1C


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    In Vitro

    In vitro activity: BI-D1870 inhibits RSK1, RSK2, RSK3 and RSK4 with an IC50 of 10–30 nM, but does not significantly inhibit ten other AGC kinase members and over 40 other protein kinases tested at 100-fold higher concentrations. BI-D1870 is cell permeant and prevents the RSK-mediated phorbol ester- and EGF -induced phosphorylation of glycogen synthase kinase-3β and LKB1 in human embry-onic kidney 293 cells and Rat-2 cells. BI-D1870 does not affect the agonist-triggered phosphorylation of substrates for six other AGC kinases. Moreover, BI-D1870 does not suppress the phorbol ester- or EGF-induced phosphorylation of CREB.

     

    Kinase Assay: Purified His6-RSK1, His6-RSK2 or GST-RSK21-389:S381E (1-2 units/mL) are assayed for 10 min at 30°C in a 50 μL assay mixture in Buffer A containing 30 μM substrate peptide (KEAKEKRQEQIAKRRRLSSLRASTSKSGGSQK), 10 mM magnesium acetate and 100 μM of [γ-32P]ATP. Reactions are terminated and analysed. The amount of enzyme that catalysed the phosphorylation of 1 nmol of substrate peptide in 1 min is termed one unit.

     

    Cell Assay: Measurement of cell growth is assessed using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay in six replicates. The cells (5×103/200 μL) are seeded in 96-well, flat-bottom plates for 24 h and then exposed to various concentrations of test agents for the indicated time intervals. After removing the culture medium, 200 μL of the medium containing MTT at a concentration of 0.5 mg/mL is added, and the cells are incubated at 37°C for 2 h. The medium is removed, and the reduced MTT dye in each well is dissolved in 200 μL DMSO. Absorbance is determined with a multimode microplate reader Synergy HT at 570 nm.

    In Vivo

    BI-D1870 (0.5 mg/kg)-injected experimental autoimmune encephalomyelitis (EAE) mice exhibits a delayed neural deficit without obvious weight loss. Histopathological analyses shows inflammatory cell infiltration and demyelination in the spinal cord in control mice, but not in BI-D1870-treated mice. BI-D1870 protects against the infiltration of TH1 or TH17 cells into the CNS.

    Animal model

    Mice

    Formulation & Dosage

    Myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 MEVGWYRSPFSRVVHLYRNGK) (BEX) is used to induce EAE in C57/BL6J mice. Mice are injecteds.c. with 200 g of MOG peptide in 100 μL of PBS emulsified in 100 μL complete Freund’s adjuvant (CFA) that is further supplemented with five mg/mL Mycobacterium tuberculosis. In addition, 500 ng pertussis toxin is injected i.p. on days zero and two. The RSK inhibitor (BI-D1870; 0.5 mg/kg) is injected i.p. into mice two days after immunization with MOG peptide, and injection is repeated every other day for 11 days. Mice that receive only dimethyl sulfoxide (DMSO) solution are used as controls. Paralysis is evaluated according to the following scale: zero, no disease; one, tail limpness; two, hind limb weakness; three, hind limb paralysis; four, fore limb weakness; five, quadriplegia; six, death. For histological analysis, CNS samples are fixed with 4% paraformaldehyde and sliced at 4 μm, and then hematoxylin & eosin (H & E) staining is performed.

    References

    Biochem J. 2007 Jan 1; 401(Pt 1): 29–38; Immunobiology. 2016 Feb;221(2):188-92.

    These protocols are for reference only. InvivoChem does not independently validate these methods.

    BI-D1870

    Structure-activity relationships for dihydropteridinone interactions with kinases and bromodomains and structural comparison of inhibitor binding modes.  2014 Apr;10(4):305-12.

    BI-D1870

    Responses of FLT3 inhibitor-sensitive and -resistant AML cell lines to TG-101348 and BET inhibitors.  2014 Apr;10(4):305-12.


    BI-D1870

    Functional activities of dual kinase/bromodomain inhibitors in primary human cell disease models. a, Test agents and kinase or BET benchmark inhibitors were tested for effects on protein biomarkers (x-axis) in 12 primary human cell-based BioMAP systems () at 7 doses.  b, BI-2536 (BI) and TG-101348 (TG) and inhibitors targeting either kinases, including JAK (tofacitinib (Tofa) and ruxolitinib (Ruxo)) or PLK (GSK-461364A (GSK)), or BET bromodomains (JQ1, I-BET, PFI-1, and I-BET 151) were profiled in the BioMAP Diversity PLUS panel at 6 doses to generate dose-specific compound signature activity profiles.



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