BI-D1870

Alias: BI D1870; BID1870; BI-D1870
Cat No.:V0238 Purity: ≥98%
BI-D1870 is a specific, cell permeable and ATP-competitive inhibitor of RSK1/2/3/4 (p90 ribosomal S6 kinase) with the potential to treatautoimmune encephalomyelitis (EAE).
BI-D1870 Chemical Structure CAS No.: 501437-28-1
Product category: S6 kinase
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product 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). In cell-free assays, it inhibits RSK1/2/3/4 with IC50 values of 31 nM, 24 nM, 18 nM, and 15 nM, respectively. and exhibits ten to one hundred times more selectivity for RSK than for MST2, GSK-3, CK1, MARK3, and Aurora B. Serine/threonine kinases known as RSKs play a role in a number of cellular functions, such as growth, survival, and motility. Additionally, BI-D1870 demonstrated in vitro strong antiproliferative activity.

Biological Activity I Assay Protocols (From Reference)
Targets
RSK4 (IC50 = 15 nM); RSK3 (IC50 = 18 nM); RSK2 (IC50 = 24 nM); RSK4 (IC50 = 15 nM); RSK1 (IC50 = 31 nM)
ln Vitro
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. In human embryonic kidney 293 cells and Rat-2 cells, BI-D1870 is cell permeant and inhibits RSK-mediated phorbol ester- and EGF-induced phosphorylation of glycogen synthase kinase-3β and LKB1. Six other AGC kinases' agonist-triggered phosphorylation of their substrates is unaffected by BI-D1870. Furthermore, BI-D1870 does not block the phosphorylation of CREB brought on by either phorbol ester or EGF.[1]
ln 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.
Enzyme Assay
Purified His6–RSK1, His6–RSK2 or GST–RSK2 1–389: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. As previously mentioned, reactions are stopped and examined. One unit of an enzyme is the quantity required to catalyze the phosphorylation of 1 nmol of a substrate peptide in one minute. In order to assay RSK and MSK1 in HEK-293 or Rat-2 cell lysates, these kinases are immunoprecipitated from the cell lysates (0.1 mg of lysate protein for RSK and 0.3 mg for MSK1) and for RSK assays the immunoprecipitates are washed twice with Buffer A containing 1 mM ATP and twice with Buffer A prior to the assay, as a precaution to ensure dissociation of BI-D1870 from the RSK isoforms.
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. In 96-well flat-bottom plates, the cells (5 103/200 L) are seeded for 24 hours before being exposed to varying concentrations of test agents for the durations of time specified. Following the removal of the culture medium, 200 L of medium containing MTT at a concentration of 0.5 mg/mL is added, and the cells are incubated at 37°C for 2 hours. Each well's reduced MTT dye is dissolved in 200 L of DMSO after the medium has been removed. Synergy HT multimode microplate reader at 570 nm is used to measure absorbance.
Animal Protocol
Myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 MEVGWYRSPFSRVVHLYRNGK) (BEX) is used to induce EAE in C57/BL6J mice. Mice are given s.c. injections of 200 g of MOG peptide emulsified in 100 μL of PBS, 100 l of complete Freund's adjuvant (CFA), and five mg/mL of Mycobacterium tuberculosis. Additionally, on days 0 and 2, 500 ng of pertussis toxin is intravenously injected. Two days after receiving the MOG peptide vaccination, mice are given an intraperitoneal injection of the RSK inhibitor (BI-D1870; 0.5 mg/kg), which is repeated every other day for 11 days. As controls, mice are given only dimethyl sulfoxide (DMSO) solution. On a scale from zero (no disease) to six (death), paralysis is rated as follows: one (tail limpness), two (hind limb weakness), three (hind limb paralysis), four (fore limb weakness), five (quadriplegia), and six (no disease). Hematoxylin and eosin (H & E) staining is carried out on CNS samples after they have been cut at a thickness of 4 m and fixed with 4% paraformaldehyde for histological analysis.
References

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

[2]. Biochem J . 2007 Jan 1;401(1):29-38.

[3]. Immunobiology . 2016 Feb;221(2):188-92.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C19H23F2N5O2
Molecular Weight
391.4150
Exact Mass
391.18198
Elemental Analysis
C, 58.30; H, 5.92; F, 9.71; N, 17.89; O, 8.18
CAS #
501437-28-1
Appearance
Pale orange to brown solid powder
SMILES
CC1C(=O)N(C2=CN=C(N=C2N1CCC(C)C)NC3=CC(=C(C(=C3)F)O)F)C
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)
Chemical Name
2-((3,5-difluoro-4-hydroxyphenyl)amino)-8-isopentyl-5,7-dimethyl-7,8-dihydropteridin-6(5H)-one
Synonyms
BI D1870; BID1870; BI-D1870
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
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 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.5548 mL 12.7740 mL 25.5480 mL
5 mM 0.5110 mL 2.5548 mL 5.1096 mL
10 mM 0.2555 mL 1.2774 mL 2.5548 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
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Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
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Biological Data
  • 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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