Ibrutinib (PCI-32765)

Catalog No.S2680

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.

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Ibrutinib (PCI-32765) Chemical Structure

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

Validation & Quality Control

Cited by 31 publications:

7 customer reviews :

Quality Control & MSDS

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Product Information

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  • Research Area
  • Inhibition Profile

Product Description

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)

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IC50 0.5 nM 0.5 nM 0.8 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.

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

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
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 2016-07-30)

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 --

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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 solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 88 mg/mL (199.77 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
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 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

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.

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