Ibrutinib (PCI-32765)

Catalog No.S2680

Ibrutinib (PCI-32765) Chemical Structure

Molecular Weight(MW): 440.5

Ibrutinib (PCI-32765) is a potent and highly selective Brutons tyrosine kinase (Btk) inhibitor with IC50 of 0.5 nM in cell-free assays, modestly potent to Bmx, CSK, FGR, BRK, HCK, less potent to EGFR, Yes, ErbB2, JAK3, etc.

Size Price Stock Quantity  
In DMSO USD 272 In stock
USD 170 In stock
USD 320 In stock
USD 970 In stock

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Cited by 31 Publications

8 Customer Reviews

  • BTK C481S and C481T variants show resistance to ibrutinib. (a and b) COS-7 cells were transfected with wild-type BTK or the two variants. Thirty-six hours post transfection, the cells were serum starved and treated with ibrutinib overnight followed by activation with serum and pervanadate for 5 min at room temperature. The cell lysates were immunoblotted for pY223 BTK and pY753 PLCγ2.

    Leukemia, 2016.. Ibrutinib (PCI-32765) purchased from Selleck.

    Identification of Btk as a potent kinase for WIP tyrosine phosphorylation. Total protein lysates were prepared from THP-1 cells that were stably transfected with wild-type WIP-EGFP and treated with PCI-32765 at the concentration specified on the blots for 2h before pervanadate treatment for 30 min. In all cases WIP-EGFP was immunoprecipitated from cell lysates using anti-EGFP antibody and membranes subsequently blotted with the pY (4G10) antibody, EGFP antibody and β-Tubulin.

    J Cell Sci 2015 128(2), 251-65. Ibrutinib (PCI-32765) purchased from Selleck.

  • Phosphorylation of ERK1/2 and AKT, but not BTK, was inhibited in sensitive but not resistant MCL cells. Western blotting of BTK phosphorylation. Mantle cell lymphoma (MCL) cells were treated with indicated doses of ibrutinib, cell lysates were collected at 1 or 4 h, and subjected to Western blotting analysis using phosphorylated BTK (p-BTK) (Y223) and total BTK (t-BTK) antibodies.

    Br J Haematol 2014 166(6), 849-61. Ibrutinib (PCI-32765) purchased from Selleck.

    Effect of Ibrutinib on CLEC-2-mediated platelet activation and signaling in humans. Washed human platelets were incubated with Ibrutinib (5 nM) for 5 min followed by stimulation with convulxin (100 ng/ml) or rhodocytin (30 nM) under stirred conditions. Platelet proteins were separated by SDS-PAGE, Western-blotted, and probed for phospho Syk (Tyr525/526) and PLCγ2 (Tyr759). β-actin was used as a lane loading control.

    J Biol Chem 2015 290(18), 11557-68. Ibrutinib (PCI-32765) purchased from Selleck.

  • BTK is expressed by malignant plasma cells and ibrutinib induces cytotoxicity in MM patient cells. (A) BTK mRNA and protein expression in control B-cells and MM patient cells and MM cell lines as measured by real-time PCR and Western blotting. (B) MM cells (n = 11) were treated with two doses of ibrutinib (1 and 10 μM), bortezomib (10 and 20 nM) and lenalidomide (1 and 10 μM) for 48 h and then assessed for cell death/proliferation by Cell Titer GLO assay. (C and D) MM cell lines were analysed for cell death in response to ibrutinib (1 and 10 μM), bortezomib (10 and 20 nM) and lenalidomide.

    Cell Signal 2013 25, 106-12. Ibrutinib (PCI-32765) purchased from Selleck.

    Ibrutinib induces increased cytotoxicity in combination with lenalidomide and bortezomib in MM patient cells. (A) MM patient cells were treated wit h various combinations of ibrutinib (1 and 10 μM), bortezomib (10 and 20 nM) and lenalidomide (1 and 10 μM) for 48 h and then assessed for cell death/proliferation by Cell Titer GLO assay. (B) MM cell lines were analysed for cell death in response to various combinations of ibrutinib (1 and 10μM), bortezomib (10 and 20 nM) and lenalidomide. (C) RPMI8226 cells were analysed for cell death in response to ibrutinib (1 and 10μM), bortezomib (20 nM) and lenalidomide (10μM) and combinations thereof, and then analysed for apoptosis using annexin-V/propidium iodide staining and flow cytometry. (D) Primary human monocytes were treated with two doses of ibrutinib (1 and 10 μM) and then in combination with bortezomib (20 nM) and lenalidomide (10 μM) for 48 h and then assessed for cell death/proliferation by Cell Titer GLO assay.

    Cell Signal 2013 25, 106-12. Ibrutinib (PCI-32765) purchased from Selleck.

  • Ibrutinib downregulates anti-apoptotic proteins and induces caspase mediated apoptosis in MM cells. (A) FLIPL , survivin and Bcl- xL mRNA expression was determined in MM patient cells and MM cell lines treated with ibrutinib (10 μM) and bortezomib (20 nM) both alone and in combination. (B) FLIPL protein expression was measured by Western blotting in extracts from RPMI8226 cells treated with ibrutinib (10μM) and bortezomib (20 nM) both alone and in combination for 8 hours. (C) The MM cell line RPMI8226 was treated with the pan caspase inhibitor zVAD-fmk (10 μM) before treatment with ibrutinib (10 μM) and borte zomib (20 nM) both alone and in combination for 48 h and then assessed for cell death/prolife ration by Cell Titer GLO assay.

    Cell Signal 2013 25, 106-12. Ibrutinib (PCI-32765) purchased from Selleck.

    Cell lines were exposed to 0, 50 and 150 mM Ibrutinib for 4 h. The level of phosphorylated ERK1/2 (p-ERK1/2) was reduced in TCF3-rearranged MHH-CALL3 compared with non-TCF3-rearranged Nalm6 and MHH-CALL4 cell lines. b-Actin served as a loading control. P-ERK/b-actin: ratio of the intensities. See Supplementary Materials and methods document for more information.

    Blood Cancer J 2014 4, e181. Ibrutinib (PCI-32765) purchased from Selleck.

Purity & Quality Control

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Notes:

2. For more details, such as half maximal inhibitory concentrations (IC50s) and working concentrations of each inhibitor, please click on the link of the inhibitor of interest.
3. "+" indicates inhibitory effect. Increased inhibition is marked by a higher "+" designation.
4. Orange "√" refers to compounds which do inhibitory effects on the related isoform, but without specific value.

Biological Activity

Description Ibrutinib (PCI-32765) is a potent and highly selective Brutons tyrosine kinase (Btk) inhibitor with IC50 of 0.5 nM in cell-free assays, modestly potent to Bmx, CSK, FGR, BRK, HCK, less potent to EGFR, Yes, ErbB2, JAK3, etc.
Targets
BTK [1]
(Cell-free assay)
BLK [1]
(Cell-free assay)
Bmx [1]
(Cell-free assay)
CSK [1]
(Cell-free assay)
FGR [1]
(Cell-free assay)
0.5 nM 0.5 nM 0.8 nM 2.3 nM 2.3 nM
In vitro

Ibrutinib shows the potent and irreversible inhibitory effect and selectivity for Btk enzymatic activity. In BCR pathway-activated DOHH2 cell line, Ibrutinib inhibits autophosphorylation of Btk, phosphorylation of Btk's physiological substrate PLCγ, and phosphorylation of further downstream kinase, ERK with IC50 of 11 nM, 29 nM and 13 nM, respectively. [1] Ibrutinib exhibits a significant dose-dependent and time-dependent induction of cytotoxicity in chronic lymphocytic leukemia (CLL) cells. In addition, Ibrutinib induces cell death depending on caspase pathway activation and antagonizes the ability of CLL cells to proliferate after TLR signaling. [2] A recent study shows that Ibrutinib inhibits BCR-activated primary B cell proliferation with IC50 of 8 nM and results in inhibition of TNFα, IL-1β and IL-6 production in primary monocytes with IC50 of 2.6 nM, 0.5 nM and 3.9 nM, respectively. [3]

In vivo In a collagen-induced arthritis model, Ibrutinib significantly reduces clinical arthritis scores reflecting paw swelling and joint inflammation by inhibiting B-cell activation. In a MRL-Fas(lpr) lupus model, Ibrutinib reduces renal disease and autoantibody production. [1] In an adoptive transfer TCL1 mouse model of CLL, Ibrutinib (25 mg/kg/day) causes a transient early lymphocytosis, and delays CLL disease progression. [4]

Protocol

Kinase Assay
+ Expand

Kinase Assays :

In vitro kinase IC50 values are measured using 33P filtration binding assay after 1 hour incubation of kinase, 33P-ATP, Ibrutinib, and substrate [0.2 mg/mL poly(EY)(4:1]. Assays are performed at Reaction Biology.
Cell Research
+ Expand
  • Cell lines: Chronic lymphocytic leukemia (CLL) cells
  • Concentrations: 0.01-100 μM
  • Incubation Time: 48 hours
  • Method:

    MTT (3'[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) assays are performed to determine cytotoxicity. Briefly, cells (CLL B cells or healthy volunteer T cells or NK cells) are incubated for 48 hours with different concentrations of Ibrutinib, or vehicle control. MTT reagent is then added, and plates are incubated for an additional 20 hours before washing with protamine sulfate in phosphate-buffered saline. Dimethyl sulfoxide is added, and absorbance is measured by spectrophotometry at 540 nm in a Labsystems plate reader. Cell viability is also measured at various time points with the use of annexin/PI flow cytometry. Data are analyzed with Expo-ADC32 software package. Results are expressed as the percentage of total positive cells over untreated control. Experiments examining caspase-dependent apoptosis includes the addition of 100μM Z-VAD.


    (Only for Reference)
Animal Research
+ Expand
  • Animal Models: MRL-Fas(lpr) lupus model and collagen-induced arthritis model.
  • Formulation: Ibrutinib is dissolved in DMSO.
  • Dosages: ≤50 mg/kg
  • Administration: Administered via p.o.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 88 mg/mL (199.77 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
In vivo 2% DMSO+Castor oil 10mg/mL

* 1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 440.5
Formula

C25H24N6O2

CAS No. 936563-96-1
Storage powder
in solvent
Synonyms N/A

Bio Calculators

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02757040 Not yet recruiting Leukemia, Lymphocytic, Chronic, B-Cell Peking University Peoples Hospital|Beijing Hospital December 2016 Phase 3
NCT02760485 Not yet recruiting Diffuse Large B-cell Lymphoma Incyte Corporation September 2016 Phase 1|Phase 2
NCT02815059 Not yet recruiting Acute Lymphoblastic Leukemia University of Utah|Janssen, LP August 2016 Phase 1
NCT02643667 Not yet recruiting Prostate Cancer Lawrence Fong|University of California, San Francisco July 2016 Phase 1|Phase 2
NCT02801578 Recruiting Chronic Lymphocytic Leukemia M.D. Anderson Cancer Center July 2016 --
NCT02756897 Recruiting Leukemia|Chronic Lymphocytic Leukemia|Small Lymphocytic Lymphoma M.D. Anderson Cancer Center|AbbVie July 2016 Phase 2

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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BTK Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID