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.
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