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Biological Activity
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Description
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CAY10505 is a PI3Kγ inhibitor with IC50 of 30 nM. |
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Targets
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PI3Kγ |
PI3Kα |
PI3Kβ |
PI3Kδ |
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IC50 |
30 nM |
0.94 μM |
20 μM |
20 μM [1] |
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In Vitro
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CAY10505 selectively inhibits PI3Kγ isoform, with an IC50 of 30 nM better than the PI3Kα, β, and δ isoforms, with IC50 of 0.94, 20 and 20 μM, respectively. Tested against a panel of 80 other kinases including casein kinase 2, CAY10505 significantly inhibits only the unrelated casein kinase 2 (CK20) with an IC50 of 20 nM. CAY10505 also inhibits the phosphorylation of the PI3K substrate PKB/Akt in mouse macrophages with an IC50 of 228 nM. CAY10505 inhibits C5a-mediated?PKB/Akt phosphorylation?in Raw-264?macrophages, with an IC50 of 0.23?nM. In human monocytic cell line THP-1, MCP-1, binding to the GPCR chemokine receptor CCR2, strongly induces phosphorylation of PKB/Akt, which is effectively inhibited by 26 at IC50 values as low as 0.4 μM. CAY10505 inhibits MCP-1-mediated chemotaxis in wild-type primary monocytes in a concentration-dependent manner with an IC50 of 52 μM, as well as in the monocytic cell line THP-1 with an IC50 of 53 μM. [1] |
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In Vivo
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Oral administration of CAY10505 at 10 mg/kg results in moderate reduction of neutrophil recruitment by 35%, almost matching the result observed in PI3Kγ-deficient mice. [1] Five weeks of deoxycorticosterone acetate salt (DOCA) administration are followed by 7 days of daily administration of PI3Kγ inhibitor CAY10505 at a dose of 0.6 mg/kg (p.o.), which significantly improves acetylcholine-induced endothelium dependent relaxation, serum nitrate and (or) nitrite level, glutathione level, and the vascular endothelial lining in hypertensive rats. [2] |
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Clinical Trials
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Features
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Protocol
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Kinase Assay
[1]
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| PI3Kγ lipid kinase assay |
A PI3Kγ lipid kinase assay, based on the neomycin-coated scintillation proximity assay (SPA) bead technology, is performed in 384-well plates using ATP/[γ33P]ATP and PtdIns as substrates. Kinase assays for IC50 value determinations of CAY10505 with PI3Kα, PI3Kβ, and PI3Kδ are carried out. |
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Cell Assay
[1]
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| Cell Lines |
Bone marrow cells |
| Concentrations |
~10 mM |
| Incubation Time |
3 hours |
| Methods |
Bone marrow cells are isolated, prepared, and stimulated. For in vitro chemotaxis, 107 5-day-derived BMDMs are suspended in 1 mL of medium containing 0.5% BSA and CAY10505 or DMSO and applied to the upper chamber of a transwell, 5 μm pore size, chemotaxis plate. An amount of 600 μL of medium containing MCP-1/CCL2 and inhibitors or DMSO is added to the lower chamber. After 3 hours of incubation at 37 °C and 5% CO2, the number of cells in the lower chamber is quantified with a Coulter. |
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Animal Study
[2]
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| Animal Models |
Wistar albino rats |
| Formulation |
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| Doses |
0.6 mg/kg |
| Administration |
Administered via p.o. |
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