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PCI-32765 (Ibrutinib)

Bruton's tyrosine kinase (BTK) inhibitor CAS# 936563-96-1

PCI-32765 (Ibrutinib)

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Chemical structure

PCI-32765 (Ibrutinib)

3D structure

Chemical Properties of PCI-32765 (Ibrutinib)

Cas No. 936563-96-1 SDF Download SDF
PubChem ID 24821094 Appearance Powder
Formula C25H24N6O2 M.Wt 440.5
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Ibrutinib
Solubility DMSO : ≥ 30 mg/mL (68.10 mM)
H2O : < 0.1 mg/mL (insoluble)
*"≥" means soluble, but saturation unknown.
Chemical Name 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one
SMILES C=CC(=O)N1CCCC(C1)N2C3=C(C(=N2)C4=CC=C(C=C4)OC5=CC=CC=C5)C(=NC=N3)N
Standard InChIKey XYFPWWZEPKGCCK-GOSISDBHSA-N
Standard InChI InChI=1S/C25H24N6O2/c1-2-21(32)30-14-6-7-18(15-30)31-25-22(24(26)27-16-28-25)23(29-31)17-10-12-20(13-11-17)33-19-8-4-3-5-9-19/h2-5,8-13,16,18H,1,6-7,14-15H2,(H2,26,27,28)/t18-/m1/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of PCI-32765 (Ibrutinib)

DescriptionIbrutinib is a potent and highly selective inhibitor of Btk with IC50 of 0.5 nM, modestly potent to Bmx, CSK, FGR, BRK, HCK, less potent to EGFR, Yes, ErbB2, JAK3, etc.
TargetsBtk    
IC500.5 nM     

Protocol

Cell experiment:

Cell lines

CLL cell lines

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.

Reacting condition

24 h,48 h and 72 h; 1 μM.

Applications

Anti-IgM–supported CLL cell viability was reduced in the presence of PCI-32765 from 69% to 33% at 24 hours, and to 31% and 29% after 48 and 72 hours, respectively. Anti-IgM stimulation induced an average 27%±12% increase in viability after 24 hours compared with unstimulated controls. Preincubation with 1 μM PCI-32765 before anti-IgM stimulation significantly reduced CLL cell viability to 98%±8% of unstimulated controls. Survival signals from NLCs were also effectively inhibited by PCI-32765.

Animal experiment:

Animal models

CB17 SCID mice and Eμ-TCL1 transgenic (Tg) mice on a C3H/BL6 background

Dosage form

Suboptimal (2.5 mg/kg/d); optimal (25 mg/kg/d)

Application

In the adoptive transfer TCL1 mouse model, animals treated PCI-32765 at 2 weeks post cell transfer with the suboptimal (2.5 mg/kg/d) and optimal (25 mg/kg/d) doses exhibited a transient lymphocytosis at day 4, with an average of 7- and 10-fold increases in circulating TCL1 leukemia cells, respectively.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1] Ponader S, Chen S S, Buggy J J, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo[J]. Blood, 2012, 119(5): 1182-1189.

PCI-32765 (Ibrutinib) Dilution Calculator

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Preparing Stock Solutions of PCI-32765 (Ibrutinib)

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.2701 mL 11.3507 mL 22.7015 mL 45.403 mL 56.7537 mL
5 mM 0.454 mL 2.2701 mL 4.5403 mL 9.0806 mL 11.3507 mL
10 mM 0.227 mL 1.1351 mL 2.2701 mL 4.5403 mL 5.6754 mL
50 mM 0.0454 mL 0.227 mL 0.454 mL 0.9081 mL 1.1351 mL
100 mM 0.0227 mL 0.1135 mL 0.227 mL 0.454 mL 0.5675 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

Research Update of PCI-32765 (Ibrutinib)

1. Ibrutinib (PCI-32765) in chronic lymphocytic leukemia. Hematol Oncol Clin North Am. 2013 Aug;27(4):851-60, x. doi: 10.1016/j.hoc.2013.01.006.
Abstract
PCI-32765, an inhibitor of Bruton tyrosine kinase, has the potential to be an integral component of CLL therapy for its inhibition against CLL cell survival and proliferation and its impacts on CLL cell migration and homing.
2. [Effect of PCI-32765 and bortezomib on proliferation and apoptosis of B-cell tumor cell lines and its mechanisms]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2013 Oct;21(5):1178-82. doi: 10.7534/j.issn.1009-2137.2013.05.018.
Abstract
PCI-32765, a Btk inhibitor, dose- and time- dependently inhibited proliferation and significantly induced apoptosis in Raji and Ramos cells; while the combination of PCI-32765 and bortezomib synergistically enhanced those effects with down-regulation of Btk, NFKB, Bcl-cl and c-IAP1 and up-regulation of caspase-3.
3. The Bruton tyrosine kinase (BTK) inhibitor PCI-32765 synergistically increases proteasome inhibitor activity in diffuse large-B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells sensitive or resistant to bortezomib. Br J Haematol. 2013 Apr;161(1):43-56. doi: 10.1111/bjh.12206. Epub 2013 Jan 30.
Abstract
The combination of PCI-32765 and bortezomib increased mitochondrial injury, apoptosis and ROS generation in DLBCL and MCL cells with minimal toxicity towards normal CD34(+) bone marrow cells.
4. The orally available Btk inhibitor ibrutinib (PCI-32765) protects against osteoclast-mediated bone loss. Bone. 2014 Mar;60:8-15. doi: 10.1016/j.bone.2013.11.025. Epub 2013 Dec 4.
Abstract
PCI-32765 inhibits both osteoclast differentiation and function leading to suppressed osteoclastic bone resorption, where it downregulates NFATc1 expression and disrupts the actin ring formation in mature osteoclasts. PCI-32765 also alleviated bone loss in an osteoporosis mouse model.

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Background on PCI-32765 (Ibrutinib)

PCI-32765, also named as Ibrutinib, is a Bruton tyrosine kinase inhibitor which is used to study the biological effects of Bruton tyrosine kinase inhibition on mature B-cell function and the progression of B cell-associated diseases in vivo. The Bruton tyrosine kinase is specifically necessary for BCR signaling as demonstrated by human and mouse mutations that disrupt Bruton tyrosine kinase function and prevent B-cell maturation at steps which need a functional BCR pathway. PCI-32765 also inhibited autoantibody production. Occupancy of the Bruton tyrosine kinase active site by PCI-32765 was monitored in vitro and in vivo using a fluorescent affinity probe for Bruton tyrosine kinase.

Reference

Lee A. Honigberga, Ashley M. Smitha, Mint Sirisawada, Erik Vernera, David Lourya, Betty Changa, Shyr Lib, Zhengying Panb,d, Douglas H. Thamme, Richard A. Millera, and Joseph J. Buggya. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. PNAS. 2010; 107(29): 13075 – 80.

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References on PCI-32765 (Ibrutinib)

The orally available Btk inhibitor ibrutinib (PCI-32765) protects against osteoclast-mediated bone loss.[Pubmed:24316417]

Bone. 2014 Mar;60:8-15.

Bone-resorbing osteoclasts play an essential role in normal bone homeostasis, as well as in various bone disorders such as osteoporosis and rheumatoid arthritis. Previously we showed that the Tec family of tyrosine kinases is essential for the differentiation of osteoclasts and the inhibition of Btk is a promising strategy for the prevention of the bone loss in osteoclast-associated bone disorders. Here we demonstrate that an orally available Btk inhibitor, ibrutinib (PCI-32765), suppresses osteoclastic bone resorption by inhibiting both osteoclast differentiation and function. Ibrutinib downregulated the expression of NFATc1, the key transcription factor for osteoclastogenesis, and disrupted the formation of the actin ring in mature osteoclasts. In addition, genome-wide screening revealed that Btk regulates the expression of the genes involved in osteoclast differentiation and function in both an NFATc1-dependent and -independent manner. Finally, we showed that ibrutinib administration ameliorated the bone loss that developed in a RANKL-induced osteoporosis mouse model. Thus, this study suggests ibrutinib to be a promising therapeutic agent for osteoclast-associated bone diseases.

The BTK Inhibitor Ibrutinib (PCI-32765) Overcomes Paclitaxel Resistance in ABCB1- and ABCC10-Overexpressing Cells and Tumors.[Pubmed:28265007]

Mol Cancer Ther. 2017 Jun;16(6):1021-1030.

Paclitaxel is one of the most widely used antineoplastic drugs in the clinic. Unfortunately, the occurrence of cellular resistance has limited its efficacy and application. The ATP-binding cassette subfamily B member 1 (ABCB1/P-glycoprotein) and subfamily C member 10 (ABCC10/MRP7) are the major membrane protein transporters responsible for the efflux of paclitaxel, constituting one of the most important mechanisms of paclitaxel resistance. Here, we demonstrated that the Bruton tyrosine kinase inhibitor, ibrutinib, significantly enhanced the antitumor activity of paclitaxel by antagonizing the efflux function of ABCB1 and ABCC10 in cells overexpressing these transporters. Furthermore, we demonstrated that the ABCB1 or ABCC10 protein expression was not altered after treatment with ibrutinib for up to 72 hours using Western blot analysis. However, the ATPase activity of ABCB1 was significantly stimulated by treatment with ibrutinib. Molecular docking analysis suggested the binding conformation of ibrutinib within the large cavity of the transmembrane region of ABCB1. Importantly, ibrutinib could effectively enhance paclitaxel-induced inhibition on the growth of ABCB1- and ABCC10-overexpressing tumors in nude athymic mice. These results demonstrate that the combination of ibrutinib and paclitaxel can effectively antagonize ABCB1- or ABCC10-mediated paclitaxel resistance that could be of great clinical interest. Mol Cancer Ther; 16(6); 1021-30. (c)2017 AACR.

The bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) blocks hairy cell leukaemia survival, proliferation and B cell receptor signalling: a new therapeutic approach.[Pubmed:24697238]

Br J Haematol. 2014 Jul;166(2):177-88.

B cell receptor (BCR) signalling plays a critical role in the progression of several B-cell malignancies, but its role in hairy cell leukaemia (HCL) is ambiguous. Bruton tyrosine kinase (BTK), a key player in BCR signalling, as well as B cell migration and adhesion, can be targeted with ibrutinib, a selective, irreversible BTK inhibitor. We analysed BTK expression and function in HCL and analysed the effects of ibrutinib on HCL cells. We demonstrated uniform BTK protein expression in HCL cells. Ibrutinib significantly inhibited HCL proliferation and cell cycle progression. Accordingly, ibrutinib also reduced HCL cell survival after BCR triggering with anti-immunoglobulins and abrogated the activation of kinases downstream of the BCR (PI3K and MAPK). Ibrutinib also inhibited BCR-dependent secretion of the chemokines CCL3 and CCL4 by HCL cells. Interestingly, ibrutinib inhibited also CXCL12-induced signalling, a key pathway for bone marrow homing. Collectively, our data support the clinical development of ibrutinib in patients with HCL.

Ibrutinib (PCI-32765) in chronic lymphocytic leukemia.[Pubmed:23915749]

Hematol Oncol Clin North Am. 2013 Aug;27(4):851-60, x.

B-cell receptor (BCR) signaling is essential for chronic lymphocytic leukemia (CLL) cell survival. Many kinases in the BCR signaling pathway are being studied as potential therapeutic targets. Ibrutinib (PCI-32765) is a novel first-in-class selective inhibitor of Bruton tyrosine kinase. Preclinical evidence suggests that ibrutinib inhibits CLL cell survival and proliferation and affects CLL cell migration and homing. Early clinical data in patients with CLL and non-Hodgkin lymphoma is encouraging. It is likely that ibrutinib and other drugs targeting the BCR pathway will become an integral component of CLL therapy.

Description

Ibrutinib (PCI-32765) is a selective, irreversible Btk inhibitor with an IC50 of 0.5 nM. Ibrutinib can be used as a Btk ligand in the synthesis of a series of PROTACs, such as P13I. P13I induces 73% degradation of Btk at 10 nM and 89% at 100 nM in human Burkitt’s lymphoma, RAMOS cells.

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