A66 is a novel small molecule inhibitor of PI3K p110α with IC50 values of 32, 30 and 43 nM for p110α, p110α/E545K and p110α/H1047R. A66, showing the S-enantiomer to be a highly specific and selective p110α inhibitor. The responsive cell lines all harboured H1047R mutations in PIK3CA and have high levels of p110α and class-Ia PI3K activity. A66 is more than 100 fold less active against the other class-I PI 3-kinase isoforms and had not inhibitory activity against 200 protein kinases when tested at 10 micromolar. This makes it the most selective and specific p110α inhibitor available for research purposes.
|Cell lines||CD4+ T lymphocytes|
|Preparation method||T lymphocyte isolation and activation
To obtain naive CD4+ T lymphocytes (CD4+CD62L+ T cells), spleens were passed through a 70 lm mesh. After centrifugation, red blood cells were lysed and the cells washed in culture medium (Click’s medium supplemented with 10% heat inactivated FCS). Then, naive CD4+ T cells were isolated using Miltenyi CD4+CD62L+ T cell isolation kit II for mouse cells (Ref. 130-093-227, Miltenyi Biotec, Bergisch Gladbach, Germany) according to the manufacturers’ instructions. The isolated cells were routinely >97% CD4+, >95% CD62L+. Cells (106) were cultured in 1 ml culture medium in 24- well culture plates (Costar) pre-coated with anti-CD3 antibody (YCD3-1, 5 lg ml 1). Where indicated, anti-CD28 (H57, 2.5 lg ml 1, eBioscience, San Diego, California), DMSO or inhibitors dissolved in DMSO (1 ll per culture) were added. At 24 h, the cultures were resuspended, centrifuged and the supernatants assayed for cytokine content.
|Concentrations||0~10 μ M|
|Incubation time||24 h|
|Animal models||mice bearing SK-OV-3, HCT-116 and U87MG xenograft models|
|Formulation||20% 2-hydroxypropyl-β-cyclodextrin (Sigma–Aldrich) in water|
|Dosages||10 ml/kg once daily (QD) or twice daily (BID) daily for 21 days or twice daily for 16 days (SK-OV-3), daily for 14 days (U87MG) and daily for 7 days (HCT-116)|
|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 ≥79 mg/mL|
ETP-46321, a dual p110α/δ class IA phosphoinositide 3-kinase inhibitor modulates T lymphocyte activation and collagen-induced arthritis.
Aragoneses-Fenoll L, et al. Biochem Pharmacol. 2016 Apr 15;106:56-69. PMID: 26883061.
Effects of acutely inhibiting PI3K isoforms and mTOR on regulation of glucose metabolism in vivo.
Smith GC, et al. Biochem J. 2012 Feb 15;442(1):161-9. PMID: 22142257.
A drug targeting only p110α can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types.
Jamieson S, et al. Biochem J. 2011 Aug 15;438(1):53-62. PMID: 21668414.
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