product name CZC24832
Description: CZC24832 is the first selective PI3Kγ inhibitor with IC50 of 27 nM, with 10-fold selectivity over PI3Kβ and >100-fold selectivity over PI3Kα and PI3Kδ. A high-throughput chemoproteomics method has benen optimized to enable multiplexed screening resulting in the finding of CZC24832. Plenty of target- and cell-based studies of CZC24832 revealed regulation of interleukin-17–producing T helper cell (TH17) differentiation by PI3Kg, therefore giving selective inhibition of PI3Kg as a potential treatment for inflammatory and autoimmune diseases.
References: Nat Chem Biol. 2012 Apr 29;8(6):576-82.
364.4
Formula
C15H17FN6O2S
CAS No.
1159824-67-5
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 5 mg/mL warming (13.72 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
0.5% CMC: 30 mg/mL
Chemical Name
5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide
other peoduct :
| In Vitro |
Kinase Assay: Competition binding assays using the LK matrix are performed essentially as described above but adapted to a 384-well format. 0.25 mg of cell lysate and 2.5 μL of beads are used per well. Compounds from the screening library including reference compounds as standards are added at 40 μM final concentration from 50× DMSO stocks. Each plate contains 15 positive and 17 negative controls. After 2 hrs binding at 4 °C, the non-bound fraction is removed by washing the beads with lysis buffer. Proteins retained on the beads are eluted in SDS sample buffer and spotted on nitrocellulose membranes (400 nL/spot) using an automated pin tool liquid transfer. After drying, the membranes are rehydrated in 20% ethanol, and processed for detection with specific antibodies as indicated, followed by incubation with a labeled secondary antibody for visualization. Spot intensities are quantified using a scanner and percentage inhibition is calculated using positive and negative controls as 100% and 0% inhibition, respectively. Cell Assay: CZC24832 has excellent selectivity to PI3Kγ. Out of the 154 identified lipid and protein kinases and the 922 other proteins, only two off targets (PI3Kβ and PIP4K2C) are detected within a 100-fold selectivity window. Despite the high sequence conservation of the human and rodent class I PI3K isoforms, the potency of CZC24832 for PI3Kγ and PI3Kβ is consistently lower by a factor of 2 to 4 in mice and rats compared to humans, but selectivity windows are largely retained. In the BT system, treatment with CZC24832 results in profound inhibition of IL-17A (IC50 =1.5 μM) as well as of B-cell activation markers such as IL-6 and IgG. In addition, strong inhibition of IL17A production is observed in T-cell systems such as human umbilical vein endothelial cells grown in the presence of TH2 blasts, indicating a general role for PI3Kγ kinase activity in the control of TH17 function. Thus, CZC24832 inhibits TH17 cell differentiation |
|---|---|
| In Vivo | In an IL-8–dependent air pouch model, CZC24832 shows a dose dependent reduction of granulocyte recruitment consistent with the degree of inhibition observed in PI3Kγ-null mice. In a therapeutic collagen induced arthritis (CIA) model, mice treated orally with 10 mg CZC24832 per kg body weight twice per day shows a substantial decrease of bone and cartilage destruction as well as of overall clinical parameters. |
| Animal model | CIA mouse model |
| Formulation & Dosage | Dissolved in 0.5% CMC in water; 3, 10 mg/kg; Oral gavage |
| References | [1] Bergamini G, et al. Nat Chem Biol, 2012, 8(6), 576-582. |
