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.
Int Immunopharmacol. 2022 Dec;113(Pt B):109469.
Ibrutinib suppresses the activation of neutrophils and macrophages and exerts therapeutic effect on acute peritonitis induced by zymosan
PCI-32765 purchased from AbMole
BMC Biol. 2021 May 20;19(1):108.
Very long intergenic non-coding (vlinc) RNAs directly regulate multiple genes in cis and trans
PCI-32765 purchased from AbMole
J Virol. 2020 Feb 14;94(5):e01791-19.
Targeting Kaposi's Sarcoma-Associated Herpesvirus ORF21 Tyrosine Kinase and Viral Lytic Reactivation by Tyrosine Kinase Inhibitors Approved for Clinical Use
PCI-32765 purchased from AbMole
Cell Experiment | |
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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). |
Concentrations | 0~100nM |
Incubation time | 7days |
Animal Experiment | |
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Animal models | RANKL-induced bone loss in mice |
Formulation | saline |
Dosages | 6.25, 12.5 or 25 mg/kg 1 h before the first GST-RANKL injection |
Administration | oral gavage |
Molecular Weight | 440.5 |
Formula | C25H24N6O2 |
CAS Number | 936563-96-1 |
Solubility (25°C) | DMSO ≥30 mg/mL |
Storage | 2-8°C, protect from light, dry, sealed |
Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
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BIIB091
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TAK-020
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