PCI-32765, a selective, irreversible Btk inhibitor, is a novel, molecularly targeted agent for patients with B-cell malignancies, and is particularly active in patients with CLL. B-cell receptor (BCR) signaling is a critical pathway in the pathogenesis of several B-cell malignancies, including chronic lymphocytic leukemia (CLL), and can be targeted by inhibitors of BCR-associated kinases, such as Bruton tyrosine kinase (Btk). PCI-32765 significantly inhibited CLL cell survival, DNA synthesis, and migration in response to tissue homing chemokines (CXCL12, CXCL13). PCI-32765 also down-regulated secretion of BCR-dependent chemokines (CCL3, CCL4) by the CLL cells, both in vitro and in vivo. In an adoptive transfer TCL1 mouse model of CLL, PCI-32765 affected disease progression. In this model, PCI-32765 caused a transient early lymphocytosis, and profoundly inhibited CLL progression, as assessed by weight, development, and extent of hepatospenomegaly, and survival. Inhibition of BTK by PCI-32765 overcomes BCR- and chemokine-controlled integrin-mediated retention and homing of malignant B cells in their growth- and survival-supporting lymph node and bone marrow microenvironment, which results in clinically evident CLL regression.
|Source||Blood (2011). Figure 3. PCI-32765|
|Cell Lines||CD19+ cells|
|Incubation Time||8 h|
|Results||We found that inhibition of caspase activity by z-VAD-fmk completely prevented the induction of apoptosis provided by PCI-32765 concurrent with a decrease in cleaved PARP expression and a decrease in enzymatic activity of caspase-3|
|Source||Blood (2011). Figure 2. PCI-32765|
|Cell Lines||CD19+ cells|
|Incubation Time||12-72 h|
|Results||We found that there were no significant differences in PCI-32765–induced cell death based on interphase cytogenetic analysis|
|Cell lines||osteoblast cells|
|Preparation method||In vitro osteoblast differentiation Cells derived from calvaria were cultured in an osteogenic medium (50 μM ascorbic acid, 10 nM dexamethasone and 10 mM β- glycerophosphate) in the presence of ibrutinib and subjected to an analysis of the activity of alkaline phosphatase (after 7 days) and bone nodule formation (after 21 days).|
|Animal models||RANKL-induced bone loss in mice|
|Dosages||6.25, 12.5 or 25 mg/kg 1 h before the first GST-RANKL injection|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|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.
|Solubility||DMSO ≥86 mg/mL|
Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies.
Advani RH, et al. J Clin Oncol. 2013 Jan 1;31(1):88-94. PMID: 23045577.
The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia.
de Rooij MF, et al. Blood. 2012 Mar 15;119(11):2590-4. PMID: 22279054.
The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells.
Chang BY, et al. Arthritis Res Ther. 2011 Jul 13;13(4):R115. PMID: 21752263.
The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy.
Honigberg LA, et al. Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13075-80. PMID: 20615965.
|Related Src-bcr-Abl Products|
TG-100572 hydrochloride is a potent and selective multi-targeted VEGFR2/Src kinase inhibitor.
Ponatinib hydrochloride is a potent, orally available multi-targeted kinase inhibitor with IC50s of 0.37 nM, 1.1 nM, 1.5 nM, 2.2 nM, and 5.4 nM for Abl, PDGFRα, VEGFR2, FGFR1, and Src, respectively.
AMG-47a is a potent inhibitor of Lck and T cell proliferation; exhibits anti-inflammatory activity (ED50 = 11 mg/kg) in the anti-CD3 induced production of IL-2 in mice.
GZD824 Dimesylate is a novel orally bioavailable Bcr-Abl inhibitor for Bcr-Abl(WT) and Bcr-Abl(T315I) with IC50 of 0.34 nM and 0.68 nM, respectively.
Radotinib is a selective BCR-ABL1 tyrosine kinase inhibitor with IC50 of 34 nM, used to treat Chronic Myeloid Leukemia.
Products are for research use only. Not for human use. We do not sell to patients.
© Copyright 2010-2017 AbMole BioScience. All Rights Reserved.