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.
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.
|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 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.
|Solubility||DMSO ≥30 mg/mL|
|Storage||2-8°C, protect from light, dry, sealed|
|Related BTK Products|
Poseltinib is an orally active, selective, irreversible small-molecule Bruton tyrosine kinase (BTK) inhibitor with an IC50 of 1.95 nM and 0.3, 2.3, and 2.4 fold selective action against BMX, TEC, and TXK, respectively. Poseltinib covalently binds to the active site of BTK (cysteine 481 residue) and effectively inhibits B cell receptor (BCR), Fc receptor (FcR), and Toll-like receptor (TLR) mediated signaling.
Vecabrutinib (SNS-062) is a potent, non-covalent BTK and ITK inhibitor,Kd The values are 0.3 nM and 2.2 nM, respectively. Vecabrutinib for ITK IC50 The value is 24 nM.
Rilzabrutinib, also known as PRN1008, is a reversible covalent, selective and oral active inhibitor of Bruton’s Tyrosine Kinase (BTK) with IC50 of 1.3 nM.
Pirtobrutinib (LOXO-305; LY 3527727; RXC-005) is a highly selective and non-covalent next generation BTK inhibitor, which inhibits diverse BTK C481 substitution mutations. Pirtobrutinib is also more than 300-fold selective for BTK versus 370 other kinases.
Remibrutinib (LOU064) is a potent and highly selective covalent Inhibitor of Bruton's Tyrosine Kinase (BTK) with IC50 value of 1 nM.
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