Ibrutinib (PCI-32765)

Ibrutinib is a potent and highly selective Btk inhibitor with IC50 of 0.5 nM, modestly potent to Bmx, CSK, FGR, BRK, HCK, less potent to EGFR, Yes, ErbB2, JAK3, etc.

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Ibrutinib (PCI-32765) Chemical Structure

Ibrutinib (PCI-32765) Chemical Structure
Molecular Weight: 440.5

Validation & Quality Control

Customer Reviews(3)

Quality Control & MSDS

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Product Information

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Product Description

Biological Activity

Description Ibrutinib is a potent and highly selective Btk inhibitor with IC50 of 0.5 nM, modestly potent to Bmx, CSK, FGR, BRK, HCK, less potent to EGFR, Yes, ErbB2, JAK3, etc.
Targets BTK [1] BLK [1] Bmx [1] CSK [1] FGR [1]

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IC50 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]
Features

Protocol(Only for Reference)

Kinase Assay:

[1]

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 Assay:

[2]

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.

Animal Study:

[1]

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.
Solubility 1% DMSO/30% polyethylene glycol/1% Tween 80, , 12 mg/mL
* 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.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Honigberg LA, et al. Proc Natl Acad Sci U S A. 2010, 107(29), 13075-13080.

[2] Herman SE, et al. Blood. 2011, 117(23), 6287-6296.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-08-23)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02207062 Not yet recruiting B-cell Chronic Lymphocytic Leukemia|Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue|Nodal Marginal Zone B-cell Lympho  ...more B-cell Chronic Lymphocytic Leukemia|Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue|Nodal Marginal Zone B-cell Lymphoma|Recurrent Adult Diffuse Small Cleaved Cell Lymphoma|Recurrent Grade 1 Follicular Lymphoma|Recurrent Grade 2 Follicular Lymphoma|Recurrent Marginal Zone Lymphoma|Recurrent Small Lymphocytic Lymphoma|Refractory Chronic Lymphocytic Leukemia|Refractory Hairy Cell Leukemia|Splenic Marginal Zone Lymphoma|Waldenström Macroglobulinemia University of Washington|National Cancer Institute (NCI) October 2014 --
NCT02219737 Not yet recruiting Recurrent Adult Diffuse Large Cell Lymphoma National Cancer Institute (NCI) August 2014 Phase 1
NCT02195869 Recruiting Graft Versus Host Disease Pharmacyclics July 2014 Phase 1|Phase 2
NCT02165397 Recruiting Waldenstrom Macroglobulinemia Pharmacyclics|Janssen Research & Development, LLC July 2014 Phase 3
NCT02169180 Not yet recruiting Lymphoma, Mantle-cell Janssen Pharmaceutical K.K. June 2014 Phase 2

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Chemical Information

Download Ibrutinib (PCI-32765) SDF
Molecular Weight (MW) 440.5
Formula

C25H24N6O2

CAS No. 936563-96-1
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms N/A
Solubility (25°C) * In vitro DMSO 88 mg/mL (199 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 1% DMSO/30% polyethylene glycol/1% Tween 80, 12 mg/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 Name (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one

Research Area

Customer Reviews (3)


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Rating
Source Cell Signal, 2013, 25(1), 106-12.. Ibrutinib (PCI-32765) purchased from Selleck
Method Western blotting/Proliferation/death assays
Cell Lines MM cell lines
Concentrations 1/10 μM
Incubation Time 48 h
Results Ibrutinib induces signifi cant cell death (7–46%) in MM cells at 10 μM(Fig. C) as measured by the Cell Titer GLO assay. We also observed a similar effect with ibrutinib in MM cell lines ( Fig. D).

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Rating
Source Cell Signal, 2013, 25(1), 106-12.. Ibrutinib (PCI-32765) purchased from Selleck
Method flow cytometry/Cell Titer GLO assay
Cell Lines RPMI8226 cells/Primary human monocytes
Concentrations 1/10 μM
Incubation Time 48 h
Results Ibrutinib significantly increased cytotoxicity of malignant plasma cells, with the effectin- vitro appearing greater in combination with bortezomib (Fig. A). We also observed a similar effect with ibrutinib in combination with either lenalidomide or bortezomi b in MM ce ll lines (Fig. B). These observations were further confirmed using an annexin-V/ propidium iodide apoptosis assay (Fig. C). Furthermore, we observed that BTK inhibition had no cytotoxic effects on primary monocytes suggesting the effect on malignant plasma cells is not through non-specific cytotoxicity (Fig. D).

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Rating
Source Cell Signal, 2013, 25(1), 106-12.. Ibrutinib (PCI-32765) purchased from Selleck
Method Western blotting/Cell Titer GLO assay/Real-time PCR
Cell Lines MM cells
Concentrations 10 μM
Incubation Time 48 h
Results We found that FLIPL, Bcl-xL and survivin are inhibited by ibrutinib alone and in combination with bortezomib (Fig. A and B). Since both FLIPL and Bcl-xL negatively regulate caspase-induced cell death we looked to establish whether cell death observed in the MM cells was the result of caspase activation. Thepan-caspase inhibitor zVAD-fmk was able to protect MM cells from cell death induced by ibrutinib alone or in co mb in ation with bortezomib establishing that ibrutinib induced MM cell death is caspase-dependent(Fig. C).

Product Citations (13)

Tech Support & FAQs

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