CAL-101 (GS-1101) is a highly selective and potent p110δ small molecule inhibitor (half-maximal effective concentration [EC(50)] = 8nM). CAL-101 inhibits CLL cell chemotaxis toward CXCL12 and CXCL13 and migration beneath stromal cells (pseudoemperipolesis). CAL-101 (GS-1101) also down-regulates secretion of chemokines in stromal cocultures and after BCR triggering. CAL-101 reduces survival signals derived from the BCR or from nurse-like cells, and inhibits BCR- and chemokine-receptor-induced AKT and MAP kinase (ERK) activation. In stromal cocultures, CAL-101 sensitizes CLL cells toward bendamustine, fludarabine, and dexamethasone. CAL-101 (GS-1101) blocked constitutive phosphatidylinositol-3-kinase signaling, resulting in decreased phosphorylation of Akt and other downstream effectors, an increase in poly(ADP-ribose) polymerase and caspase cleavage and an induction of apoptosis. CAL-101 displays a dual mechanism of action, directly decreasing cell survival while reducing interactions that retain CLL cells in protective tissue microenvironments.
|Source||Cancer Biol Med (2015). Figure 5. CAL-101|
|Cell Lines||Z138, HBL-2, and Jeko-1 cells|
|Incubation Time||48 h|
|Results||CAL-101 exhibited a time-dependent inhibitory effect on the viability of Z138, HBL-2, and Jeko-1 cells. CAL-101 and BTZ concentrations were fixed at 60 and 0.18 μmol/L, respectively|
|Cell lines||Primary cortical neurons, astrocytes or microglia|
|Preparation method||Assaying TNF secretion For drug treatments, cells were incubated with IC87114 (Symansis), CAL-101 (Active Biochem, #A-1138) and LPS, glucose-free Locke’s buffer (GD), or a combination thereof. For TNF surface delivery assay18, 32, TNF-converting enzyme inhibitor was added at the same time as LPS or included in the glucose-free Locke’s buffer (GD). All inhibitors were reconstituted in dimethylsulphoxide (Sigma) with final concentrations <0.1% in assays. To determine the levels of secreted TNF, a commercial BD OptEIA TNF Elisa Set II (#558534) kit (BD Biosciences) was used to quantify cytokine concentration in samples according to the manufacturer’s instructions.|
|Animal models||wild-type (WT) or p110δD910A/D910A mice|
|Dosages||CAL-101 (40 mg k−1g i.v.) 15 min before ischaemia (CAL-101, Pre) or 3 h after reperfusion (CAL-101, Post)|
|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 80 mg/mL|
PI3Kδ inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma.
Meadows SA, et al. Blood. 2012 Feb 23;119(8):1897-900. PMID: 22210877.
The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia.
Hoellenriegel J, et al. Blood. 2011 Sep 29;118(13):3603-12. PMID: 21803855.
CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability.
Lannutti BJ, et al. Blood. 2011 Jan 13;117(2):591-4. PMID: 20959606.
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